Conditions: Adenoid Cystic Carcinoma
Keywords: Adenoid Cystic Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 18
Healthy volunteers: no

Brief summary:
This research is studying how safe and effective all-trans retinoic acid (ATRA), is to treat advanced adenoid cystic carcinoma (ACC).

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved all-trans retinoic acid (ATRA) for this specific disease but it has been approved for other uses.

The main purpose of this study is to see how effective all-trans retinoic acid (ATRA) is in treating tumor. Other reasons for conducting the study are:

* To determine for how long all-trans retinoic acid (ATRA) may reduce the size or slow down the growth of tumor
* To evaluate levels of circulating tumor DNA (ctDNA) released in the bloodstream as an indication of the disease activity
* To better understand mechanisms of tumor resistance to ATRA

Arms:
arm 1: -Participants will receive Tretinoin orally divided over two daily doses for days 1 through 14 of a 28-day cycle

Interventions: intervention 1: Tretinoin
Intervention descriptions: intervention 1: ATRA control normal cell growth, cell differentiation (the normal process of making cell different from each other), and cell death during embryonic development and in certain tissues later in life. Retinoids effects on the cells are controlled by receptors on the nucleus of each cell (nuclear receptors)

Protocol document:
SAP_004.pdf: 
NCI Protocol #:  Not applicable 
 
NCT03999684 
 
Date of document: December 31, 2019 
 
DF/HCC Protocol #: 19-224  
 
TITLE:  A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic 
carcinoma 
 
STATISTICAL PLAN 
 


STATISTICAL CONSIDERATIONS 
 
Original Design When Trial Opened. 
The trial was originally designed as a two-stage one arm phase II trial with primary endpoint of 
best overall response with n=14 patients who are eligible and begin protocol treatment to be 
entered into the first stage. Details of the original design as follows: 
 
The primary endpoint of this study is best overall response rate (CR+PR). A Simon two-stage 
design will be used to minimize the number of patients exposed to this regimen and the specific 
sample size and operating characteristics were chosen to be able to show that the response rate is 
greater than 10% (that found in prior studies) and closer to 28%.  Fourteen eligible patients who 
start protocol treatment are to be accrued in the first stage. If there are ≤ 1 of 14 patients with 
disease in response, accrual to this trial will be closed with the expectation that there is little 
evidence that the response rate will reach 28%. The probability that the trial will close early is 58% 
if the true response rate is 10%. If there are >1 patients with disease in response, accrual will 
continue until a total of 25 eligible patients who start protocol treatment are entered. If > 4 of 25 
patients who are eligible and begin protocol treatment have disease in response, then this regimen 
will  be considered worth further study. The probability of concluding that the regimen is worth 
further study is 85% if the true response rate is 28%. The probability of concluding that the regimen 
is worth further study is 9% if the true response rate is 10%. Allowing 2 patients to be entered and 
then declared ineligible and/or to not start protocol treatment, the overall accrual goal is 27.  
 
Amendment 3: Details, Rational and Design: 
 
Fourteen patients (eligible and began protocol streatment) have been entered into stage 1 for the 
original design when the trial opened and now referred to as ‘Cohort 1’.  Due to preliminary results 
of low efficacy in Cohort 1, accrual to Cohort 1 is suspended and n=6 additional patients (‘Cohort 
2’) are to be entered to assess safety and tolerability of continuous daily dosing. The choice of n=6 
is due to lack of concerning SAEs in Cohort 1 as well as to keep within the constraints of original 
budget and its corresponding drug availability for the testing of continuous dosing. For Cohort 2, 
AEs plan to be continuously monitored and best overall response assessed. With n=6 eligible 
patients who being protocol treatment, the lower limit of one-sided 90% exact binomial 
confidence interval will be greater than 10% (the null hypothesis in the original design) if at 
least 3 patients have disease in response (CR or PR). All aspects of the AE profile and outcome 
of these 6 patients are to be assessed with decisions made regarding amending the trial for 
any further design changes and continuation or closure of accrual. The table below gives the 
lower limit of one-sided 90% exact binomial confidence interval based on various scenarios. 
 
Sample 
size 
Cohort 2 
# of patients with 
disease in response 
Lower limit of one-
sided 90% CI 
6 
2 
9.2% 
6 
3 
20.1% 
 
 
 
  
 
 


Analysis and Accrual Estimates 
The primary efficacy population includes all eligible patients who begin protocol treatment. Best 
overall response will be summarized as a proportion with a corresponding exact 95% confidence 
interval (CI).  
 
For secondary objectives:  
• Adverse events will be classified and graded according to the CTCAE v.5.0. Frequencies 
of adverse events will be summarized among patients who begin protocol therapy.  
 
• The distributions of time-to-event endpoints will be estimated using the Kaplan-Meier 
method with corresponding 95% confidence intervals for the median or time-specific event 
time.  
 
With an estimated monthly accrual of 2 patients, accrual to the first stage (Cohort 1) is estimated 
to take approximately 7-8 months to accrue n = 15 (of which n = 14 who are eligible and who 
begin protocol treatment).  Estimated monthly accrual to Cohort 2 is estimated to be similar (1-2 
patients per month). Due to possible delays in initiation of approval and/or in initiation of accrual 
itself, accrual could take longer.  As is customary with this type of design, accrual will be 
suspended after the first stage (Cohort 1, n = 14 eligible patients who begin protocol therapy) in 
order to assess outcome; however, this suspension is also dependent on the actual observed accrual 
rate and the number of patients with confirmation of disease response status while the first stage 
of the trial is accruing. Accrual to Cohort 2 would be suspended when n=6 eligible patients who 
begin protocol therapy are entered. 
 

Prot_002.pdf: 
Page 1
NCI Protocol #:  Not applicable
DF/HCC Protocol #: 19-224 
TITLE:  A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic 
carcinoma
Coordinating Center:
Dana-Farber Cancer Institute, 
                                                      450 Brookline Avenue, Boston, MA 02215
Principal Investigator (PI):
Glenn J. Hanna, M.D.
Dana-Farber Cancer Institute
glenn_hanna@dfci.harvard.edu 
Co-Investigators:
Leonard I. Zon, M.D.
Boston Children’s Hospital
leonard.zon@enders.tch.harvard.edu 
Jong C. Park, M.D.
Massachusetts General Hospital
JPARK73@mgh.harvard.edu 
Robert I. Haddad, M.D.
Dana-Farber Cancer Institute
robert_haddad@dfci.harvard.edu 
Statistician: Anne O’Neill, M.S.
Agent: All-trans retinoic acid (ATRA); generic name: Tretinoin; trade name: Vesanoid®
IND Holder: Glenn J. Hanna, M.D.
Protocol Type / Version # / Version Date: Original/February 26, 2019


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
SCHEMA
Patients with advanced or metastatic 
adenoid cystic carcinoma (ACC)*
 
Key Eligibility:
•
Histologically confirmed 
diagnosis of ACC regardless of 
MYB fusion status
•
1 or more measurable lesions (≥ 1 
cm)
•
Clinical or radiographic disease 
progression within the last 12 
months
•
Any number of prior lines of 
systemic therapy
•
ECOG performance status 0-1
•
Adequate organ and bone marrow 
function
* pre- and on-treatment tumor biopsies are required, if safe and feasible (a post-
treatment biopsy at the time of disease progression will be offered)
Primary endpoint: objective response rate (ORR) by RECIST v1.1
Secondary endpoints: progression-free survival (PFS), overall survival (OS), changes in 
MYB expression among tumor cells and circulating tumor (ct)DNA
ATRA, by mouth, in 
two divided doses, 
daily, on
Days 1-14
Cycle length: 28 days
Treatment until: 
disease progression 
or 
unacceptable 
toxicity
Follow-up at a 
minimum of: 
every 8 weeks 
through 3 years from 
the time of study 
registration
Off
Days 15-28
ATRA, by mouth, in two divided doses, daily, on
Days 1-28
Treatment until: 
disease progression 
or 
unacceptable 
toxicity
Follow-up at a 
minimum of: 
every 8 weeks 
through 3 years from 
the time of study 
registration
Cohort 1
Cohort 2


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
2
TABLE OF CONTENTS
SCHEMA
1
1.
OBJECTIVES 4
1.1
Study Design............................................................................................................4
1.2
Primary Objectives...................................................................................................4
1.3
Secondary Objectives...............................................................................................4
2.
BACKGROUND ..............................................................................................................................4
2.1
Study Disease(s).......................................................................................................4
2.2
IND Agent: Tretinoin (All-trans retinoic acid, ATRA)...........................................6
2.3
Rationale ..................................................................................................................8
2.4
Correlative Studies Background ............................................................................10
3.
PARTICIPANT SELECTION........................................................................................................11
3.1
Eligibility Criteria..................................................................................................11
3.2
Exclusion Criteria ..................................................................................................12
3.3
Inclusion of Women and Minorities ......................................................................13
4.
REGISTRATION PROCEDURES ................................................................................................13
4.1
General Guidelines for DF/HCC Institutions ........................................................13
4.2
Registration Process for DF/HCC Institutions.......................................................14
4.3
General Guidelines for Other Investigative Sites ..................................................14
4.4
Registration Process for Other Investigative Sites.................................................14
5.
TREATMENT PLAN.....................................................................................................................14
5.1
Treatment Regimen................................................................................................14
5.2
Pre-Treatment Criteria ...........................................................................................15
5.3
Agent Administration.............................................................................................17
5.4
General Concomitant Medication and Supportive Care Guidelines......................18
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................18
5.6
Duration of Follow-Up ..........................................................................................19
5.7
Criteria for Taking a Participant Off Study ...........................................................19
6.
DOSING DELAYS/DOSE MODIFICATIONS.............................................................................20
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .........................................22
7.1
Expected Toxicities................................................................................................22
7.2
Adverse Event Characteristics...............................................................................22
7.3
Adverse Event Reporting.......................................................................................23
7.4
DF/HCC Adverse Event Reporting Guidelines.....................................................24
7.5
Reporting to the Food and Drug Administration (FDA) .......................................24
7.6
Reporting to Hospital Risk Management...............................................................25
7.7
Routine Adverse Event Reporting .........................................................................25
8.
PHARMACEUTICAL INFORMATION.......................................................................................25


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
3
8.1
Study Agent: Tretinoin ..........................................................................................25
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .....................................................27
9.1
Evaluating Changes in Tumor MYB Expression in Response to Tretinoin..........28
9.2
Evaluating Circulating Tumor (ct)DNA in Response to Tretinoin........................29
10.
STUDY CALENDAR ....................................................................................................................30
11.
MEASUREMENT OF EFFECT.....................................................................................................32
11.1
Antitumor Effect – Solid Tumors ..........................................................................32
12.
DATA REPORTING / REGULATORY REQUIREMENTS........................................................38
12.1
Data Reporting.......................................................................................................38
12.2
Data Safety Monitoring..........................................................................................38
12.3
Multi-Center Guidelines ........................................................................................39
12.4
Collaborative Agreements Language.....................................................................39
13.
STATISTICAL CONSIDERATIONS............................................................................................39
14.
PUBLICATION PLAN ..................................................................................................................40
15.
REFERENCES 41
APPENDIX A
PERFORMANCE STATUS CRITERIA .............................................................43
APPENDIX B
INFORMATION ON POSSIBLE DRUG INTERACTIONS Tretinoin..............44
APPENDIX C                  Tretinoin DOSING TABLE ...............................................................................45
APPENDIX D               INFORMATION FOR PARENTS/CAREGIVERS FOR GIVING TRETINOIN46
APPENDIX E
Required specimens, processing and shipment instructions for biomarker, correlative 
and special studies...........................................................................................................................47
APPENDIX F 
Study participant self-administration instructions................................................49


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
4
1.
OBJECTIVES
1.1
Study Design
This is an open-label, single arm, phase II study of tretinoin (all trans retinoic acid, ATRA) in 
patients with advanced, unresectable, or recurrent/metastatic adenoid cystic carcinoma (ACC). All 
participants will have evidence of disease progression, or lack of benefit from standard therapies. All 
participants will have measurable disease amenable to disease monitoring. Participants in Cohort 1 
will receive tretinoin 45 mg/m2 orally divided over two daily doses for 14 days of a 28-day cycle 
until disease progression or unacceptable toxicity. Participants in Cohort 2 will receive tretinoin 45 
mg/m2 orally divided over two daily doses continuously during a 28-day cycle until disease 
progression or unacceptable toxicity. Our aim is to evaluate the anti-tumor activity of tretinoin by 
inhibition of MYB expression in advanced ACC patients. Correlative studies are planned to evaluate 
the effect of tretinoin on MYB expression in tumor tissue before and after dosing, and to measure 
circulating tumor (ct)DNA in serum samples while on therapy.
1.2
Primary Objectives
To evaluate the anti-tumor activity of tretinoin by evaluating the best overall response rate using 
RECIST v1.1 in participants with advanced adenoid cystic carcinoma.
1.3
Secondary Objectives

To estimate progression-free survival (PFS) and overall survival (OS)

To estimate duration of therapeutic response

To evaluate the inhibitory effect of tretinoin on MYB expression in ACC tumors

To evaluate ctDNA as a biomarker of disease activity in ACC based on response to therapy

To develop novel patient-derived tumor xenograft (PDX) models from MYBL1-rearranged 
ACC tumors to understand mechanisms of resistance to tretinoin
2.
BACKGROUND
2.1
Study Disease(s)
Adenoid cystic carcinoma (ACC) is a common malignancy arising often in salivary gland tissue, 
often affecting patients with no identifiable risk factors. Localized disease is generally managed with 
oncologic resection followed by adjuvant radiotherapy in most cases, given the potential for 
perineural invasion (PNI) linked with this malignancy [1, 2]. Concurrent adjuvant 
chemoradiotherapy is sometimes offered to mitigate the risk of locoregional recurrence, but no 
prospective trials have proved that this strategy is beneficial in terms of disease control rates and 
survival [3]. Despite initial multimodality therapy in the upfront setting, nearly half of ACC patients 
develop distant, metastatic spread of disease; but the natural history of such cancers is often 
reflective of slower growth velocity despite recurrences that involve the lungs, liver and bones [4]. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
5
There remain no approved systemic cytotoxic or targeted therapies available for the treatment of 
salivary gland cancers broadly, and none specifically for ACC. While some agents have 
demonstrated modest disease activity, there has been no overall or progression-free survival 
advantage observed with any particular agent(s) – therefore the optimal regimen remains unclear [5]. 
Cytotoxic chemotherapy combinations using anthracyclines, platinum and fluoropyrimidines, and 
vinorelbine in some combination may have some benefit in a limited number of ACC patients, but 
their expected toxicities and lack of durable response make them less than appealing when 
considering that patients with ACC can have slow growing, metastatic tumor burden but maintain a 
favorable quality of life over months to years [6, 7]. The Table below summarizes response rates 
among ACC patients treated with various cytotoxic regimens [5]. While combination therapies result 
in greater response rates, there is no clear survival advantage to such an approach and they come 
with toxicity. Although immune checkpoint blockade has revolutionized cancer immunotherapy with 
the success of PD-1 inhibitors in a host of solid tumors, ACC does not generally express the ligand 
of PD-1 (PD-L1) and appears to maintain minimally 
immunogenic potential [8]. Early studies investigating 
PD-1 blockade in all salivary cancer patients have been 
largely disappointing with response rates < 15% in 
selected PD-L1+ salivary tumors [9].
More recent approaches to treatment have incorporated 
molecular and genomic profiling data. While no driver 
mutation is known, these tumors have a low somatic 
mutation rate when compared with other histologic 
subtypes of cancer. Multi-targeted tyrosine kinase 
inhibitors (TKIs) such as sorafenib, and oral therapies 
targeting 
c-kit 
(imatinib, 
dasatinib) 
have 
been 
investigated with limited objective response rates (< 
15%) [10-12]. Next-generation sequencing data has 
suggested frequent alterations in a diverse array of signaling pathways including: epigenetic 
modifiers, DNA damage and repair signals, NOTCH pathway, and FGF-IGF-PI3K signaling [13]; 
and clinical trials are ongoing to evaluate the anti-
tumor effects of drugs aimed at modifying these 
aberrant signaling cascades in ACC.
One molecular aberration that has been identified 
in sequenced ACC tumors is the MYB-NFIB 
fusion 
oncogene 
generated 
by 
a 
t(6;9) 
translocation which occurs in up to 70-90% of 
ACC tumors (Figure upper right) [13, 14]. More 
than just generating MYB gene fusion transcripts, 
studies have shown that MYB mRNA is 
overexpressed among some of these tumors – 
pointing to the importance of this molecular event 
in ACC. Despite the identification of MYB has an 
important target in ACC, no MYB inhibitors have 
been identified. Zon and colleagues recently ran a 
Chemotherapy
# of 
responses/total 
patients
Response 
rate (%)
Cisplatin
2/32
6
Vinorelbine
2/13
15
Mitoxantrone
5/50
10
Epirubicin
2/20
10
Paclitaxel
0/14
0
Cyclophosphamide + 
doxorubicin + cisplatin
12/43
28
Cisplatin + anthracycline 
+ 5-FU
6/19
32
Cisplatin + vinorelbine
4/9
44
Carboplatin + paclitaxel
2/10
20
Cisplatin + gemcitabine
2/10
20


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
6
chemical screen for bioactive molecules against a MYB reporter assay in an animal model and 
identified retinoic acid compounds, including tretinoin as a potential MYB-inhibitory agent [15]. 
Therefore, evaluating the anti-tumor activity of tretinoin in advanced ACC patients seems a logical 
next-step in understanding the therapeutic potential of retinoic acids in this disease. Given historical 
objective response rates of single-agent chemotherapy and multi-targeted TKIs approaching 10% or 
less, we aim to evaluate if tretinoin may produce similar or superior response rates in advanced 
ACC.
2.2
IND Agent: Tretinoin (All-trans retinoic acid, ATRA)
2.2.1
Tretinoin
2.2.1.1
Mechanism of action
The retinoids are a pharmacologic class consisting of vitamin A (retinol) and related derivatives. 
Retinol and its metabolites play a critical role in cell growth, vision, reproduction, and epithelial cell 
differentiation, along with immune function [16]. Tretinoin is a natural retinol metabolite formed 
from intestinal oxidation of beta-carotene and from tissue anabolism of retinaldehyde. Normal serum 
concentrations are 10-20 nanomolar (nM) [17] which is 10 to 100-fold less than the retinoid 
concentrations achieved with pharmacologic therapy [18]. 
The MYB family of transcription factors is implicated in cell growth and proliferation, having been 
linked to leukemic transformation as MYB blocks differentiation of hematopoietic cells in preclinical 
models [19, 20]. Moreover, targeting of MYB with antisense oligonucleotides blocks hematopoiesis 
and therefore myeloid leukemic cell proliferation [21]. Expression of MYB declines in retinoic acid-
treated myeloid leukemic cells, which suggests that the retinoic acid receptor (RAR) partakes in the 
downregulation of MYB expression [22]. A physical interaction appears to exist between MYBi and 
the RAR, while little is actually known about the details of these mechanistic processes [23].
2.2.1.2
Preclinical safety
The HL-60 cell line is derived from an individual with acute promyelocytic leukemia (APML) which 
proliferates in vivo with a dominance of promyelocytes. Early preclinical experiments with tretinoin 
showed that differentiation (as measured morphologically) was induced at drug concentrations as 
low as 1 nM, a value 1/500th to 1/160,000th the concentration of butyrate and dimethyl sulfoxide that 
similarly promote increased differentiation among promyelocytes [24].
2.2.1.3
Clinical pharmacology and safety
Plasma levels of tretinoin after oral administration can be somewhat variable. Following a 45 mg/m2 
oral dose of tretinoin, peak plasma concentrations on the first day of dosing range from 0.1 to 8 M, 
with median concentrations of approximately 1 M. Plasma and urinary concentrations of the parent 
compound of tretinoin and metabolites was quantified in 13 patients by reverse-phase high-
performance liquid chromatography, showing that mean peak plasma levels of tretinoin were around 
347 ng/mL and were reached within 1-2 hours after ingestion. Elimination of tretinoin appears rapid 
with a terminal half-life of around 45 minutes with a monoexponential decay [25, 26]. The only 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
7
metabolite detected in plasma or urine was 4-oxo-all-trans RA which accounted for less than 10% of 
the circulating drug levels in plasma, and less than 1% in urine. No drug was detected in 
cerebrospinal fluid. Continued oral administration of tretinoin was associated with a decrease in the 
plasma peak levels and area under the concentration-time curve when measured 2-6 weeks on 
treatment. It should be noted that this decrease is associated with an increase in urinary excretion of 
the 4-oxo-all-trans RA metabolite which suggests some degree of drug catabolism over time [18]. 
While these limitations have resulted in intravenous (IV) formulations being developed, plasma 
concentrations appear similar to oral dosing in nonhuman primate models, with a similar decline in 
plasma area under the curve (AUC) as soon as three days into dosing [27].
Further studies have investigated intermittent dosing schedules (7 days on/7 days off) and have 
shown that plasma AUC declines significantly during the first week of administration from a mean 
AUC of 145 M*min on day 1 to a mean of 4 M*min on day 7. But, plasma tretinoin 
concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to 
those achieved on day 1 of therapy. Thus, intermittent schedules of administration appear to 
circumvent the low plasma drug exposure that results from sustained upregulation of catabolism that 
has been observed with daily dosing schedules [28]. This was the rationale for on/off dosing in 
Cohort 1.
Since tretinoin appears to partially induce its own metabolism, research has focused on inhibitors of 
tretinoin to combat resistance in APML [29]. Tretinoin is subject to hydroxylation by the 
cytochrome P450 26A1 isoform (CYP26A1), thus studies have attempted to inhibit tretinoin 
metabolism by administering ketoconazole or liarozole – despite their known toxicity profiles. This 
strategy has even been labeled retinoic acid metabolism blocking agents (RAMBAs) to enhance the 
clinical efficacy of tretinoin.
The toxicity profile of tretinoin is usually minor and includes headache, low grade temperatures, 
generalized weakness and some component of fatigue – seldom are any of these effects permanent or 
irreversible. Common toxicity reported in > 10% of treated patients with tretinoin include: peripheral 
edema (52%), headache (86%), malaise (66%), skin rash or dry red skin (54%), dry mucus 
membranes or nasal stuffiness, chapped lips (50%), elevated liver function tests, enzymes or 
bilirubin (50%), ostealgia (77%), or low-grade temperatures (78%) [30, 31]. While uncommon, other 
significant adverse events have been reported: venous thrombosis and myocardial infarction have 
been reported in patients without cardiac risk factors, and the risk of thrombosis (arterial or venous) 
appears increased within the first month of therapy. CNS effects such as dizziness, headaches or 
malaise have been reported. Hypertriglyceridemia or hypercholesterolemia has been reported in a 
number of patients which appears reversible following discontinuation of therapy. Pseudotumor 
cerebri (benign intracranial hypertension) has been reported, especially in children. Tretinoin has a 
high-risk of teratogenicity [32, 33]. Importantly, the two serious side effects of differentiation 
syndrome and hyperleukocytosis are only observed when tretinoin is used to treat APML. 
2.2.1.4
Clinical efficacy
As early as 1996, data was published that established the clinical safety and efficacy of tretinoin in 
the management of patients with de novo APML. One early protocol utilized a dose of 15-20 
mg/m2/day in 27 patients with newly diagnosed disease and demonstrated a 92% clinical complete 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
8
response (CR) rate among 26 evaluable patients within 13-67 days of tretinoin therapy [34]. No 
cases of retinoic acid syndrome (RAS) or hemorrhagic disseminated intravascular coagulation (DIC) 
were observed. These data supported the use of low-dose tretinoin in leukemic patients. A further 
protocol evaluated the efficacy and safety of tretinoin along to induce remission among 53 children 
with APML. The overall CR rate was 81% with an estimated 5-year disease-free survival (DFS) of 
41% and overall survival (OS) of 69% [35]. Moreover, 10-year follow-up of the cohort revealed that 
OS rates were stable. 
Tretinoin has also been successfully and safely combined with chemotherapy. The North American 
Intergroup regimen is comprised of tretinoin plus daunorubicin (an anthracycline) plus cytarabine 
(AraC) using the standard 45 mg/m2/day divided dosing until CR; demonstrating overall CR rates of 
90%, and when followed by arsenic trioxide (ATO) consolidation, event-free survival was 80% and 
OS 86% at 3-years [36]. In the AIDA protocol, tretinoin is combined with idarubicin alone (another 
anthracycline) but without AraC. Remission rates approached 95% and again utilized the same 
tretinoin dosing at 45 mg/m2/day followed by both consolidation and maintenance therapy with an 
event-free survival at 12 years of 69% [37]. In hopes of avoiding chemotherapy altogether, the Lo-
Coco regimen combined tretinoin with ATO at similar dosing and despite shorter follow-up yielded 
a > 85% remission rate, therefore supporting its role in managing low-to-intermediate risk APML 
patients, or in those who should not receive anthracycline-based therapy [38]. Combining tretinoin, 
ATO and gemtuzumab ozogamicin appears to yield response rates of 92%, with an estimated 3-year 
survival of 85% -- although toxicity has been a concern with an 8% rate of disease-related 
complications leading to death with this particular regimen [39]. In terms of long-term dosing, as 
part of consolidation and maintenance therapy for APML, tretinoin is dosed at 45 mg/m2/day orally 
days 1-7 during consolidation, and 45 mg/m2 orally daily on an intermittent schedule of 15 days on 
every 3-months or 7 days every 2 weeks for up to 1-year during the maintenance phase [36].
2.3
Rationale
Adenoid cystic carcinoma (ACC) is the second most common salivary gland malignancy, with 
nearly 1,200 new cases per year in the United States [40]. Over the past decade, genomic 
characterization of ACC tumors has highlighted recurrent translocations that involve the MYB or 
MYBL1 genes in upwards of 90% of ACCs [13, 14]. Alterations in MYB have been implicated in a 
variety of cancers, including leukemia, pediatric glioma and colonic adenocarcinomas, as well as in 
cancers of the colon, breast and prostate; but more recently, ACC-specific MYB translocations have 
been shown to promote transformation in genetically engineered mouse models [41, 42].
To date, no FDA-approved therapies exist for ACC, and no clinical MYB inhibitors have been 
identified. However, given the near universal prevalence of MYB or MYBL1 activation in ACC 
tumors, targeting of MYB/L1 remains an attractive therapeutic strategy for ACC patients. 
Translocations involving MYB have been previously described in ACC for bringing strong enhancers 
into close proximity of the MYB locus, and these enhancers are also bound by MYB protein, resulting 
in a positive feedback loop that drives MYB7 [13, 43]. Mandelbaum and colleagues at our institution 
recently undertook a chemical screen of bioactive molecules in an in vivo MYB reporter assay in 
zebrafish, and identified the retinoic acid class of compounds, including tretinoin/all-trans retinoic 
acid (ATRA), as potential MYB-inhibitory agents [44]. Specifically, c-myb:GFP-expressing cells 
from 72-hpf transgenic embryos were treated for 6 hours with 1 M of retinoic acid agonists. RA 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
9
agonists induced a rapid decline in c-myb and GFP transcript expression. Further, while ACC cell 
lines are not currently available, U937 human cells (a myeloid leukemia line over-expressing c-myb) 
showed downregulation of c-myb expression within 1 hour of tretinoin treatment in a dose-
dependent manner. 
In vivo treatment of tretinoin further reduced the growth of human ACC primagraft models in mice. 
The schematic below [Figure, below] shows (A) the experimental design for ACC xenograft 
transplantation, (B) the percentage of tumor growth inhibition among treatment groups with RA 
compounds, (C) and the final average tumor growth inhibition across three human tumors with RA 
treatments. The authors were able to show that continuous dosing was required to maintain response, 
as discontinuation of tretinoin resulted in tumor resurgence in ACC x6, x9.
Tretinoin was mechanistically found to interrupt the autoregulatory enhancer loop that occurs with 
fusion genes involving MYB, thus dramatically lowering the level of the oncogenic fusion protein 
[Figure, below]: (A) Chromosomal rearrangements that maintain MYB over-expression in ACC are 
shown with MYB, RAR-binding, and H3K27ac profiles shown at the MYB locus or downstream of 
NFIB exon 9 in ACC x9 tumors that have MYB-NFIB translocations. Previously described 
translocated MYB-bound enhancers are labeled En1 and En2. We observed a strong decrease in MYB 
binding due to tretinoin treatment at two translocated enhancers in the downstream region of NFIB 
that is fused to the MYB locus in one of the ACC primagraft models (ACC x9). In addition, there 
was a concomitant decrease in H3K27ac (marking active enhancers) at these enhancer sites. Upon 
tretinoin treatment, we found that retinoic acid receptor alpha (RAR) binds physically at the 5’ 
region of the MYB gene and at the translocated enhancer, and we confirmed that these sites have 
RAR binding motifs as determined by the JASPAR database [45]. Tretinoin stimulated increased 
RAR expression due to positive autoregulation by the bound receptor; these elevated RAR levels 
cause suppression of MYB gene expression or displaces MYB binding. Therefore, RAR expression 
appears 
to 
serve 
as 
a 
marker 
of 
response 
to 
tretinoin. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
10
These findings taken together, plus the existing FDA approval of tretinoin for APML, and its known 
tempered toxicity profile, together provide a strong rationale for testing whether tretinoin elicits a 
clinical benefit in ACC patients via MYB inhibition. Our goal for this project is to translate the basic 
and preclinical findings for the use of tretinoin in ACC to the clinic.
2.4
Correlative Studies Background
As part of this clinical study using tretinoin in advanced ACC, we will examine proof of the 
mechanism of tretinoin in ACC patient-derived tumor specimens, and further aim to identify 
candidate biomarkers and mechanisms of resistance to this novel therapy. We expect that 
interrogation of paired tumor specimens and correlation with clinical response will elucidate the 
inhibitory effects of tretinoin on MYB in ACC, therefore revealing possible mechanisms of activity 
and resistance. We will uncover novel biomarkers of response or resistance to MYB-directed therapy 
in ACC patients, by interrogating a repository of tumor tissue and peripheral blood obtained from 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
11
tretinoin-treated ACC patients. Establishing the first MYBL1-rearranged and tretinoin-resistant PDX 
models will yield insights into possible mechanisms of tretinoin activity and resistance.
We intend to interrogate circulating tumor (ct)DNA as a biomarker of ACC activity and of response 
to tretinoin therapy. Sensitive techniques have been developed recently for analyzing such “liquid 
biopsies”, to monitor ctDNA and circulating tumor cells (CTCs) as surrogate markers for tumor 
burden [46]. These techniques, in combination with imaging studies, offer a valuable approach for 
assessing tumor response. Tracking tumor-associated genetic aberrations in the blood can also be 
employed to assess residual disease, or to detect the emergence of cancer cells that are resistant to 
the therapy; and monitoring genetic alterations found in the blood plasma can be utilized to detect 
local recurrence or distant metastasis, as early as 5-10 months before they are detectable by 
conventional imaging [47, 48]. In the proposed study we aim to establish the utility of ctDNA as a 
biomarker in ACC. This is the first application of ctDNA as a marker of response to MYB-directed 
therapy in ACC, and will pave the way for future studies to validate ctDNA as a predictor of disease 
burden and clinical outcomes.
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to participate in 
the study: 
1. Participants must have histologically confirmed adenoid cystic carcinoma with evidence of 
recurrent, metastatic or advanced, unresectable disease that is not amenable to curative 
surgery with or without radiotherapy.
2. Participants must have at least one RECIST v1.1 measurable non-CNS based lesion, as 
defined as at least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions)  1 
cm with CT scans or MR imaging.
3. Participants must be willing to undergo fresh tissue core needle biopsy prior to study 
registration and repeat tumor biopsy while on study for correlatives. Willingness to provide 
blood samples for research throughout the study is also required.
4. Prior systemic therapy: At least 2 weeks must have elapsed since the end of prior 
chemotherapy, biological agents (4 weeks for anti-cancer monoclonal antibody containing 
regimens) or any investigational drug product, with adequate recovery of treatment-related 
toxicity to NCI CTCAE Version 5.0 grade ≤ 1 (or tolerable grade 2) or back to baseline 
(except for alopecia or neuropathy). Any number of prior therapies for recurrent/metastatic 
ACC are permitted. 
5. Be ≥ 18 years of age on day of signing informed consent. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A). 
7. Participants must have documentation of a new or progressive lesion on a radiologic imaging 
study performed within 12 months prior to study registration (progression of disease over any 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
12
interval is allowed) and/or new or worsening disease-related symptoms within 12 months 
prior to study registration. This assessment is performed by the treating investigator. 
Evidence of progression by RECIST v1.1 criteria is not required.
8. Participants must have normal organ and marrow function as defined below (within 14 days 
prior to study registration):

leukocytes
≥ 3,000/mcL

absolute neutrophil count
≥ 1,500/mcL

hemoglobin
≥ 9 g/dL without transfusion within 7 days of treatment

platelets
≥ 100,000/mcL

total bilirubin
≤ 2x upper limit of normal (ULN)

AST(SGOT)/ALT(SGPT)
≤ 2.5x institutional ULN or ≤ 5x ULN for those with
liver metastases

serum creatinine
≤ 1.5x ULN
OR

creatinine clearance
≥ 60 mL/min/1.73 m2 for participants with creatinine levels 
above 1.5x ULN

coagulation profile
INR ≤ 1.5x ULN unless the participant is receiving an 
anticoagulant

triglyceride level
< 500 mg/dL or < 5.7 mmol/L

cholesterol level
< 400 mg/dL or < 10.34 mmol/L
9. Baseline tumor measurements must be documented from imaging within 28 days prior to 
study registration. Other non-laboratory tests must be performed within 28 days prior to  
study registration.
10. Female subjects of childbearing potential should have a negative urine or serum pregnancy 
test within 14 days of study registration. Female subjects of childbearing potential should 
have a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the 
first dose of study medication. If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required.
11. Female and male subjects of childbearing potential must agree to use an adequate method of 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, 
for the duration of study participation, and 4 months after completion of tretinoin 
administration. Contraception is required before starting the first dose of study medication 
through 120 days after the last dose of study medication. Note: Abstinence is acceptable if 
this is the usual lifestyle and preferred contraception for the subject. There is a significant 
risk of fetal malformation if pregnancy occurs while on tretinoin at any dose level, even 
if for short exposure periods.
12. Be willing and able to provide written informed consent for the trial.
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
13
1. Metastatic disease impinging on the spinal cord or threatening spinal cord compression. 
Patients that have had previous treatment of disease with impinging on the cord with either 
surgery or radiotherapy with clinical or radiographic evidence of response or stability are 
eligible. 
2. Participant has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least four weeks prior to the 
first dose of trial treatment), and have no evidence of new or enlarging brain metastases. This 
exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability, because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other adverse 
events. 
3. Concurrent administration of other cancer specific therapy or investigational agents during 
the course of this study is not allowed. 
4. Uncontrolled intercurrent illness including but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
5. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer.
6. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
7. Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. Pregnant women are excluded from 
this study because tretinoin has the potential for teratogenic or abortifacient effects. 
Breastfeeding should be discontinued if the mother is treated on this protocol. Women who 
could potentially become pregnant while undergoing treatment on this protocol must be 
willing to use 2 methods of contraception. 
 
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial. Women, minorities and 
other underrepresented populations are all at risk to develop adenoid cystic carcinoma. 
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
14
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
4.3
General Guidelines for Other Investigative Sites
Not applicable.
4.4
Registration Process for Other Investigative Sites
Not applicable.
5.
TREATMENT PLAN
5.1
Treatment Regimen
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications are described in Section 6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy during the course of treatment.
Participants in Cohort 1 will receive tretinoin 45 mg/m2 orally divided over two daily doses for days 
1 through 14 of a 28-day cycle (tretinoin will be held on days 15 through 28 of every cycle) until 
disease progression or unacceptable toxicity. Participants in Cohort 2 will receive tretinoin 45 
mg/m2 orally divided over two daily doses continuously during a 28-day cycle until disease 
progression or unacceptable toxicity. Treatment duration is planned for 24 months or 2 years total. 
Following the first cycle of therapy, tretinoin cycles continue every 28 days or 4-weeks. The pills 
should be taken with food (preferably with a fat-containing meal). 
The first day of each cycle requires a lipid panel (fasting is not required). After completing the study 
assessment, participants will take the dose with food.
Note: Tretinoin capsules are available in a 10 mg size interval only. Doses ending in  5 mg should 
be rounded down to the nearest 10 mg and doses > 5 mg should be rounded up to the nearest 10 mg 
[e.g. 172 would round down to 170 mg; 176 would round up to 180 mg]. The higher dose of an 
uneven dose will be the AM or morning dose.


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
15
Tretinoin compliance will be monitored as part of the study. Each participant will be required to 
maintain a medication diary of each dose of medication. The medication diary will be returned to the 
clinic study staff at the end of each 28-day cycle.
5.2
Pre-Treatment Criteria
5.2.1
Cycle 1, Day 1
Eligibility and exclusion criteria are provided in Section 3. These criteria will be assessed within 28 
days of the first day of study treatment to establish eligibility and baseline values. 
Informed consent will be obtained after the study has been fully explained to the subject and before 
the conduct of any screening procedures or assessments. If screening assessments occur within 3 
days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 visit, and 
Cycle 1 Day 1 labs do not need to be performed. 
Demographic information and baseline characteristics will be collected at the Screening Visit. 
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance with 
prevailing regulations). Baseline characteristics will include ECOG performance status (Appendix 
A), disease status, medical histories, and prior and concomitant medications. 
Additional testing required, as per Section 10, includes: hematology panel (see Table 1), chemistry 
panel, fasting lipid panel, coagulation panel, urine or serum HCG (in women of childbearing 
potential; see Section 3 for when serum HCG testing is required), and an ECG. 
Table 1. Clinical Laboratory Testing
Category
Test
Hematology panel
Hematocrit, hemoglobin, platelet count, white 
cell count with differential (bands, basophils, 
eosinophils, lymphocytes, monocytes, 
neutrophils), absolute neutrophil count
Chemistry panel
Chloride, potassium, sodium, BUN, serum 
creatinine, phosphorus, calcium, albumin, total 
protein, alkaline phosphatase, ALT, AST, total 
bilirubin (Note: the frequency of checking 
magnesium levels is at the discretion of the 
treating provider)
Lipid panel
(fasting is not required) to include a 
triglyceride, LDL, HDL, and total cholesterol 
values
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
16
A fresh tumor sample should be collected prior to the start of tretinoin therapy in all patients, 
utilizing a core needle technique. Archival tissue is not permitted. A blood specimen for correlative 
studies is also needed prior to the start of tretinoin therapy.
Further details about collection and handling of tumor biopsy and blood specimens can be found in 
Section 9 and appendices.
5.2.2
Subsequent Cycles 
Reasonable effort should be made to conduct study visits on the day scheduled ( 3 days). 
Any changes from screening clinical evaluation findings that meet the definition of an adverse event 
(AE) will be recorded on the AE page of the eCRF. 
The participants ECOG performance status, weight (in kilograms), vital signs, interval history since 
the last visit, and physical examination are performed at each study visit. Concomitant medications 
should also be reviewed at each study visit. In addition, the adverse event (AE) grid should be 
completed at each study visit. All laboratory values should be reviewed before proceeding with an 
additional cycle of treatment. Participants will undergo every-28 day or every 4-week assessments 
while on study (which coincides with the start of each cycle of therapy). The drug diary for the prior 
cycle should be reviewed at each study visit by the clinical staff.
5.2.3
Additional On-treatment Assessments
Tumor Assessments:
Tumor assessments will be performed according to RECIST v1.1 (see Section 11), at baseline and 
with response evaluations performed every 8 weeks (every 2 cycles), or as clinically indicated. In the 
case of response, confirmatory scans will be performed at least 4 weeks after initial response every 8 
weeks after the scan that documented the initial response. In the case of progressive disease, 
confirmatory scans are recommended between 4-8 weeks following the date of initial progression. 
Continued treatment after initial progression is permitted, provided the patient is thought to be 
deriving clinical benefit and is counseled regarding the risks and benefits of continued treatment. If 
progression is confirmed, the date of progression is dated as the time of the original scans for study 
monitoring purposes.
Research Blood Sample Collections:
Specific instructions for research blood sample collections and draw handling are described in 
Sections 9 and 10, and Appendices. 
Tumor Biopsy Collections:
Details about collection and handling of tumor biopsy specimen can be found in Section 9 and 10,  
and Appendices. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
17
5.2.4
End-of-treatment Procedures
End-of-Treatment Visit:
All subjects will be asked to return to the site for a final, end-of-treatment visit, if possible. This visit 
must be performed within 30 days of final administration of study treatment. End-of-treatment 
assessments will not have to be repeated if the same assessments were performed within 7 days of 
this planned visit. The subject will be followed for 30 days after the last study intervention for 
adverse events.
The reason for the study participant coming off therapy should be clearly documented. For any 
reason other than for progression of disease, tumor assessments should be performed every 8-12 
weeks if a patient comes off the study drug within 1 year of enrollment. 
The participants ECOG performance status, weight (in kilograms), vital signs, interval history since 
the last visit, and physical examination are performed at the end-of-treatment visit. Concomitant 
medications should also be reviewed at this visit. In addition, the adverse event (AE) grid should be 
completed at this visit.
5.3
Agent Administration
Tretinoin administration:
All-trans retinoic acid (tretinoin) will be administered by trained medical personnel at the 
investigational site. Treatment compliance will be monitored through documentation of study 
treatment administration in the subject’s medical record. 
Doses of tretinoin at initial and subsequent dosing should use actual (not ideal or adjusted) body 
weight for calculation of dose.
Tretinoin will be administered orally as an outpatient in two divided daily doses (no in clinic dosing 
is required). The drug should be taken with food (ideally fat-containing to promote absorption). The 
dose each day of therapy should be given roughly 12 hours apart  30 minutes (suggested timing: 
8:00 AM and then again at 8:00 PM daily). Participants should try to avoid shortened or prolonged 
dosing intervals when possible. If a dose of tretinoin is missed by  6 hours from the last oral dose, 
then the next dose should be retimed for the morning of the following day. Any dose of tretinoin that 
was missed less than 6 hours from the last administration should be taken, and the following dose 
retimed for the morning of the following day. If tretinoin is not tolerated, or vomiting results in loss 
of the ingested dose, the dose should be skipped, and the next planned dose attempted when 
possible. The study drug may be crushed, chewed, or dissolved if necessary.
At each study or on-treatment visit (occurring every 28-days or every cycle), the dose of tretinoin 
should be recalculated again if there is > 5% change in body weight or body surface area (BSA) per 
institutional standard practice. Additional intravenous hydration is not required at study visits. An 
observation period is not required since dosing occurs outside the clinic setting.


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
18
5.4
General Concomitant Medication and Supportive Care Guidelines
5.4.1
Concomitant Medication Guidelines
Acceptable Concomitant Medications:
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 
Palliative radiation therapy can be prescribed and considered beyond Cycle 3 or in subsequent cycles 
at the discretion of the overall study PI, if clinically indicated. Pertinent concomitant medications 
will be recorded on the case report form (CRF). If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
Prohibited Concomitant Medications:
Azole antifungal medications may increase tretinoin toxicity due to inhibition of cytochrome P450 
metabolism of tretinoin, and thus toxicities (including pseudotumor cerebri and renal dysfunction) 
should be monitored closely during its concomitant use. Investigational agents other than tretinoin. 
There are no prohibited therapies during the post-treatment follow-up phase.
5.4.2
Supportive Care Guidelines
The following treatments are permitted throughout the duration of the study treatment phase and 
during follow-up: 
Standard therapies for pre-existing medical conditions unless listed as prohibited 
therapy below. Any medication intended solely for supportive care (e.g., analgesics, 
anti-diarrheal, anti-depressants) may be used at the investigator’s discretion. At the 
discretion of the investigator, prophylactic antiemetic and anti-diarrheal medication(s) 
may be used as per standard clinical practice before subsequent doses of study drugs.
Anticoagulants: anticoagulation with heparin, heparin derivatives, and/or warfarin may 
be given at the discretion of the treating physician. Coagulation parameters should be 
checked at each cycle, or more frequently at the discretion of the treating physician.
Pain medications administered per standard clinical practice are acceptable while the 
patient is enrolled in the study. 
Patients who experience toxicities should be treated symptomatically as clinically indicated. 
Medications that are considered necessary for the subject’s welfare and that are not expected to 
interfere with the evaluation of study treatment or be restricted may be given at the discretion of the 
investigator. Ancillary treatments will be given as medically indicated. 
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies:


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
19

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s), see Section 6.0

Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Pregnancy
Participants will be removed from the protocol therapy when any of these criteria apply.  The reason 
for removal from protocol therapy, and the date the participant was removed, must be documented in 
the case report form (CRF). Alternative care options will be discussed with the participant.
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore.
5.6
Duration of Follow-Up
Participants will be followed for best overall response and development and documentation of first 
disease progression and for survival throughout the course of the trial for 3 years from the time of 
study registration. Participants removed from protocol therapy for unacceptable adverse event and if 
they have not developed first disease progression at time of discontinuation of protocol therapy, will 
continue to be followed until first disease progression and survival until death or 3 years from study 
registration (whichever occurs first). Participants removed from protocol therapy for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.
5.7
Criteria for Taking a Participant Off Study
Participants will also be removed from study when any of the following criteria apply:
 Lost to follow-up
 Withdrawal of consent for data submission
 Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. In addition, the study team will ensure Off Treatment/Off Study information is updated 
in OnCore in accordance with DF/HCC policy REGIST-101.


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
20
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Glenn J. Hanna, MD, at Partners pager 46231. 
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated below. The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and within 30 days of the last study intervention. Participants 
continuing to experience toxicity at the last scheduled study visit may be kept on the study until the 
toxicity has resolved, or until the toxicity is deemed irreversible. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g. elective surgery, unrelated medical events). Subjects should be placed 
back on study therapy within 1 week or 7 days of any dosing interruption (dosing does not need to 
be held prior to planned surgery or procedures), unless otherwise discussed with the Principal 
Investigator. The reason for interruption should be documented in the patient's study record.
Commonly observed toxicities with tretinoin include hepatotoxicity (increased AST and ALT), 
neurologic changes including headache or pseudotumor cerebri (see below), dermatology/skin 
changes and others including cheilitis, epistaxis, fatigue, musculoskeletal pain, and conjunctivitis. 
If a patient experiences a Grade ≥ 3 toxicity that is felt to be related to tretinoin, then tretinoin will 
be held, until the toxicity has resolved to the Grade 1 level. At that time restart tretinoin at 25% dose 
reduction (or 33.75 mg/m2/day divided twice daily) or Dose level -1 (see Table 2). Dosing of 
tretinoin should be as close as possible to 33.75 mg/m2/day divided twice daily, i.e., rounded to the 
nearest 10 mg. Doses ending in  5 mg should be rounded down to the nearest 10 mg and doses > 5 
mg should be rounded up to the nearest 10 mg [e.g. 172 would round down to 170 mg; 176 would 
round up to 180 mg]. If necessary, the AM or morning dose may differ from the PM or afternoon 
dose to deliver a total daily dose as close as possible to 33.75 mg/m2/day divided twice daily. 
Recurrent episodes of Grade ≥ 3 toxicity will result in discontinuation of the tretinoin until the 
toxicity resolves to Grade ≤ 1; tretinoin can then be resumed with an additional 25% reduction (50% 
total dose reduction, Dose level -2) in the tretinoin dose (22.5 mg/m2/day divided twice daily). 
Dosing of tretinoin should be as close as possible to 22.5 mg/m2/day divided twice daily; rounded to 
the nearest 10 mg. Doses ending in  5 mg should be rounded down to the nearest 10 mg and doses 
> 5 mg should be rounded up to the nearest 10 mg [e.g. 172 would round down to 170 mg; 176 
would round up to 180 mg]. The higher dose of an uneven dose will be the AM or morning dose.


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
21
Patients experiencing Grade ≥ 3 toxicity attributable to tretinoin while on 22.5 mg/m2/day of 
tretinoin should have tretinoin held until the toxicity resolves to Grade ≤ 1. Tretinoin will then be 
resumed at the same 50% dose reduction (22.5 mg/m2/day divided twice daily) while continuing to 
monitor for toxicity and holding doses as needed for Grade ≥ 3 toxicity. Please notify the study 
overall PI about patients experiencing Grade ≥ 3 toxicity while on 50% dose reduction. Patients with 
3 episodes of Grade 3+ toxicity should be considered for therapy discontinuation in discussion with 
the overall PI.
If patients whose doses are reduced by 25% (33.75 mg/m2/day divided twice daily) or 50% (22.5 
mg/m2/day divided twice daily) tolerate the lower dose for 7 days without recurrence of the toxicity 
that led to dose adjustment, a dose escalation may be attempted. If the patient had been decreased to 
50% dosing (22.5 mg/m2/day divided twice daily) and tolerates an escalation to 75% dosing (33.75 
mg/m2/day divided twice daily) for an additional 7 days, another escalation back to 100% dosing (45 
mg/m2/day divided twice daily) may be attempted.
Tretinoin can be held on study up to 28 days or the length of one full cycle for toxicity reasons, at 
which point the patient should be removed considered for therapy discontinuation in discussion with 
the overall PI.
Pseudotumor cerebri
Pseudotumor cerebri (PTC) must be confirmed by proper history, exam and other clinically relevant 
studies. Symptoms and/or signs of PTC include headache, papilledema, visual field defects (ocular 
or visual), and absence of focal neurological symptoms, except for occasional cranial nerve (CN) VI 
palsy. Cerebrospinal fluid should be evaluated and should be negative for signs of infection. 
However, lumbar puncture should be avoided while active coagulopathy is present. An opening 
pressure should be obtained; a pressure > 200 mm water helps to establish the diagnosis of PTC. A 
CT or MRI of the brain (to evaluate for meningitis, intracranial bleed, intracranial thrombosis, etc.) 
should be performed and should be compatible with PTC. Neurological and ophthalmologic 
consultations should be obtained in order to assist in making the proper diagnosis. Carefully follow 
the visual field status of the patient. One should also strongly consider obtaining an MRI/MRV to 
exclude the possibility of a sagittal sinus thrombosis. Consider acetazolamide (Diamox) therapy and 
periodic lumbar puncture with therapeutic removal of cerebrospinal fluid as appropriate for age/size.
If PTC develops:

Hold tretinoin until this toxicity improves to Grade 0 or 1 (“mild” headache)

Restart tretinoin at 75% of the original dose (33.75 mg/m
2/day divided twice daily). If PTC 
reoccurs, hold tretinoin as above and then resume at 50% of original dose (22.5 mg/m
2/day 
divided twice daily

If the patient tolerates reduced dosing for more than 7 days, dose re-escalation can be 
attempted. Dose escalation from 50% (22.5 mg/m
2/day divided twice daily) to 75% (33.75 
mg/m
2/day divided twice daily) to 100% (45 mg/m
2/day divided twice daily) at 7 day 
intervals may be attempted if clinically appropriate.


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22
Table 2. Dose De-escalation Schema:
Dose Level
Tretinoin Dose
-2
22.5 mg/m2/day, two divided doses
-1
33.75 mg/m2/day, two divided doses
0
45 mg/m2/day, two divided doses
Note:  All treatment modifications must be expressed as a specific dose or amount rather than as a 
percentage of the starting or previous dose.
Tretinoin Dosing Should be Delayed if any of the following are present:

Grade 3 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities

Grade 3 skin, drug-related adverse event

Grade 3 drug-related laboratory abnormality, with the following exceptions: 

Grade 3 lymphopenia

Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication.
 
Unacceptable Toxicity Warranting Drug Discontinuation:

Any grade 4 adverse event will require permanent discontinuation with the following
exceptions:
Grade 4 electrolyte abnormalities that are < 72 hours in duration
Grade 4 neutropenia or lymphopenia which are < 5 days in duration
Grade 4 elevation in cholesterol or triglycerides
The consideration to re-initiate study therapy under these exceptions will be made on a case by
case basis after considering the overall benefit/risk profile and in consultation with the overall PI. 
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 
7.2) will determine whether the event requires expedited reporting in addition to routine reporting.
7.1
Expected Toxicities
Virtually all patients treated with tretinoin experience some drug related toxicity, especially 
headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible 
nor do they usually require interruption of therapy. Please see the Package Insert at the bottom of the 
protocol document for details.
7.2
Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 


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23
copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which is 
provided.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.3
Adverse Event Reporting 
7.3.1
In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the PI.
7.3.2
PI must report any adverse event (AE) that occurs after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment on the local institutional 
SAE form. 
7.3.3
Serious Adverse Events
7.3.3.1
Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

Results in death

Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe)

Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect 

Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 


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24
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 

Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the study 
drug is an SAE. 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always 
serious by regulatory definition, these events must be handled as SAEs.
Any component of a study endpoint that is considered related to study therapy should be reported as 
an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported).
7.3.3.2
Reporting SAEs
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of 
dosing. All SAEs should be followed to resolution or stabilization.
7.4
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human Research 
Studies (OHRS) per the DFCI IRB reporting policy.
Other investigative sites will report AEs to their respective IRB according to the local IRB’s policies 
and procedures in reporting adverse events. A copy of the submitted institutional AE form should be 
forwarded to the Overall PI within the timeframes detailed in the table below:  
DF/HCC Reportable Adverse Events(AEs)
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events.
7.5
Reporting to the Food and Drug Administration (FDA)


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25
The PI, as study sponsor, will be responsible for all communications with the FDA. The PI will 
report to the FDA, regardless of the site of occurrence, any serious adverse event that meets the 
FDA’s criteria for expedited reporting following the reporting requirements and timelines set by the 
FDA.
7.6
Reporting to Hospital Risk Management
PI will report to local Risk Management office any participant safety reports, sentinel events or 
unanticipated problems that require reporting per institutional policy. 
7.7
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity case 
report forms.  AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) 
must also be reported in routine study data submissions.
8.
PHARMACEUTICAL INFORMATION
Information in Section 8 is based on the Teva Pharmaceuticals USA, Inc. package insert.
8.1
Study Agent: Tretinoin
All-trans retinoic acid (ATRA); generic name: Tretinoin; trade name: Vesanoid®
8.1.1
Description
Tretinoin, USP is a retinoid that induces maturation of acute promyelocytic leukemia (APL) cells 
in culture. It is available in a 10 mg gelatin capsule for oral administration. Each capsule contains 
the following inactive ingredients: butylated hydroxyanisole, edetate disodium, gelatin, 
hydrogenated vegetable oil, polysorbate 80, soybean oil, vitamin E, and white wax (beeswax). The 
ingredients in the capsule shell include black iron oxide, red iron oxide, titanium dioxide and 
yellow iron oxide. The ingredients in the edible imprinting ink include D&C yellow no. 10 
aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red 
no. 40 aluminum lake, iron oxide black, propylene glycol and shellac glaze.
Chemically, tretinoin, USP is all-trans retinoic acid and is related to retinol (Vitamin A) and has 
the following chemical name: 3,7-Dimethyl-9-(2,6,6-trimethyl-1- cyclohexen-1-yl)-2,4,6,8-
nonatetraenoic acid. It is a yellow to light orange crystalline powder, and has the following 
structural formula:


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26
8.1.2
Form
Tretinoin Capsules are available as:
10 mg: Two-piece hard gelatin capsule with brown opaque cap and dark yellow opaque body, filled 
with yellow viscous oily suspension. Imprinted in black ink with stylized barr 808. 
Available in bottles of 100 capsules (NDC 0555-0808-02).
8.1.3
Storage and Stability
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as 
required). It is permissible for DF/HCC site to dispense ordered quantity of tretinoin in standard 
amber prescription bottle.
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
PROTECT FROM LIGHT.
8.1.4
Availability
Tretinoin is commercially available. 
8.1.5
Administration
Tretinoin will be administered by trained medical personnel at the investigational site. Treatment 
compliance will be monitored through documentation of study treatment administration in the 
subject’s medical record. 
Doses of tretinoin at initial and subsequent dosing should use actual (not ideal or adjusted) body 
weight for calculation of dose. The higher dose of an uneven dose will be the AM or morning dose.
Tretinoin will be administered orally as an outpatient in two divided daily doses (no in clinic dosing 
is required). The drug should be taken with food (ideally fat-containing to promote absorption). The 
dose each day of therapy should be given roughly 12 hours apart  30 minutes (suggested timing: 
8:00 AM and then again at 8:00 PM daily). Participants should try to avoid shortened or prolonged 
dosing intervals when possible. If a dose of tretinoin is missed by  6 hours from the last oral dose, 


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then the next dose should be retimed for the morning of the following day. Any dose of tretinoin that 
was missed less than 6 hours from the last administration should be taken, and the following dose 
retimed for the morning of the following day. If tretinoin is not tolerated, or vomiting results in loss 
of the ingested dose, the dose should be skipped, and the next planned dose attempted when 
possible. The study drug may be crushed, chewed, or dissolved if necessary.
At each study or on-treatment visit (occurring every 28-days or every cycle), the dose of tretinoin 
should be recalculated again if there is > 5% change in body weight or body surface area (BSA) per 
institutional standard practice. Additional intravenous hydration is not required at study visits. An 
observation period is not required since dosing occurs outside the clinic setting.
8.1.6
Ordering
Tretinoin, 10 mg capsules will be sourced locally by DF/HCC pharmacy site, and DF/HCC 
pharmacy site will be reimbursed via study fund.
8.1.7
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the tretinoin, using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage).
8.1.8
Destruction and Return
Unused and expired supplies of tretinoin will be destroyed on site per institutional SOP.
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Background information on the pre-clinical and clinical rationale for these investigations is 
discussed in Section 2.0 above.
Research blood sample collections should occur at the following time points: (1) at baseline, within 
14 days prior to Cycle 1 Day 1 of protocol therapy (ideally as close to administration of Cycle 1 Day 
1 therapy as possible), (2) at the beginning of every new Cycle, following C1 (expected to occur 
every 28-days) for the first 12 cycles or 1 year on treatment.
If tumor is accessible by surgical or percutaneous approach, a tumor biopsy should be performed at 
the following time points: (1) at baseline, within 28 days of Cycle 1 Day 1 of protocol therapy 
(ideally as close to administration of Cycle 1 Day 1 therapy as possible) but before the 
administration of the first dose of study treatment. (2) After cycle 2 (8 weeks on treatment), within 
14 days of the start of Cycle 3 Day 1 of protocol therapy – providing the procedure is considered 
safe, feasible, and accessible at the discretion of the treating investigator.
In all patients in whom a tumor deposit is safely accessible, a baseline tumor biopsy is required prior 
to the start of tretinoin treatment. In addition, an on-treatment biopsy will be required at after Cycle 


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28
2 (or 8 weeks into treatment), within 14 days of the start of Cycle 3 Day 1 of protocol therapy – 
providing the procedure is considered safe, feasible, and accessible at the discretion of the treating 
investigator. Patients may also be offered an end-of-treatment biopsy if the reason for 
discontinuation was progressive disease – again if safe and feasible.
9.1
Evaluating Changes in Tumor MYB Expression in Response to Tretinoin
9.1.1
Collection and Handling of Specimens
Research biopsy kits will be provided by the Zon laboratory. 
Biopsies should not be performed on Friday afternoons, as there may not be time for processing of 
the fresh tissue. If a biopsy must be performed on Friday morning, the lab of Dr. Leonard Zon must 
be notified ahead of time to ensure that there will be adequate time for processing fresh tissue, since 
fresh tissue cannot be stored over the weekend. The specimens in formalin may be stored over the 
weekend and delivered on Monday to the Zon lab. Specimens in formalin should be stored at room 
temperature until processing.
Ideally two core biopsies will be obtained at each biopsy timepoint:
• Two cores should be placed in 10% neutral buffered formalin tube supplied by the study team
After being obtained, processing of the cores is as follows:
• All samples should be de-identified and labeled with the participant initials, participant study ID 
number and date of procedure.
All leftover tissue will be banked in the laboratory of Dr. Leonard Zon, such that it can be used for 
additional or optional future analyses as needed:
Dr. Leonard Zon
Karp Research Building, 7th Floor 
300 Longwood Ave. Boston, MA 02115 
Telephone: 617-919-2069, Fax: 617-730-0222
9.1.2
Specimen Processing and Analysis
Paired tumor biopsies of each participant will also be analyzed by ChIP- and ATAC-seq, to identify 
changes in MYB and RAR binding to chromatin and evaluate chromatin accessibility at relevant 
regions; the goal is to study molecular changes that can be correlated with response to treatment. We 
have observed that RAR protein levels are enhanced in the xenograft tumors that are treated with 
tretinoin for 28 days; as such, this enhancement would serve as an excellent marker of the action of 
the treatment on the tumor. Most patients in this study will also have had their tumor genomically 
characterized by a targeted next-generation sequencing platform (DFCI Oncopanel, formerly 
protocol#11-104, now #17-000) at the time of enrollment. Changes in MYB expression and MYB 
gene activation (translocation status) will be correlated with clinical response and patient outcomes. 
To identify mechanisms of resistance, we will use whole-exome sequencing (WES) to evaluate the 
tumors of patients who achieve clinical benefit, and who have undergone an optional biopsy at the 


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29
time of disease progression, in order to determine the acquisition of novel genomic alterations from 
activation of other signaling pathways and/or from epigenomic changes. We expect to generate at 
least one MYBL1-rearranged PDX model, because about 10% of ACCs harbor MYBL1 fusions and 
take rates are about 50-60%. A second PDX model will also be generated from ACC tumors with 
primary or secondary resistance to tretinoin.
9.2
Evaluating Circulating Tumor (ct)DNA in Response to Tretinoin
9.2.1
Collection and Handling of Specimens
Research blood specimens should not be performed on Friday afternoons, as there may not be time 
for processing of the sample. If a collection must be performed on Friday morning, the lab of Dr. 
Jens Lohr must be notified ahead of time to ensure that there will be adequate time for processing, 
since these samples should not be stored over the weekend. 
Laboratory of Jens G. Lohr, M.D., Ph.D., Dana-Farber Cancer Institute, Dana Building, Room 542, 
450 Brookline Avenue, Boston, MA 02215, Phone: (617) 632-2069, Pager: 42255
Ideally three blood specimen tubes will be obtained at each collection timepoint:
• Two 10 mL purple-top (EDTA) tubes and one 10 mL Streck tube for circulating tumor (ct)DNA 
and CTC studies
After being obtained, processing of the blood samples should follow the instructions provided in 
Appendix E
9.2.2
Specimen Processing and Analysis
We will first determine the cancer fraction of ACC in circulating tumor (ct) or cell-free (cf)DNA 
across disease stages. We will isolate cfDNA from the blood of ACC patients treated with tretinoin, 
before treatment, and at the time specified in the study calendar.  The serum from all of these 
samples will be isolated, sequencing libraries prepared, and next-generation sequencing performed. 
Data will be segmented, normalized and bias-corrected, using a custom pipeline. The ACC fraction 
and the total amount of ACC-derived DNA in cfDNA will be determined at the above time points. 
The ACC-derived cfDNA fraction, and the total circulating ACC DNA concentration, will be 
correlated with established clinical parameters of ACC disease burden. In selected patients, we will 
determine ACC DNA fraction and concentration at very early time points to quantify rapid increases 
of cfDNA as a consequence of the effective killing of ACC cells, as well as later time points. We 
will establish whether cfDNA can be used as a quantitative tumor marker of treatment response, 
identify the copy-number variations in cfDNA, and quantify how many subclones have a distinct 
copy-number profile. The TITAN algorithm [49] or other computational analysis tools will be 
applied to determine the clonal composition of ACC-derived cfDNA, and the outgrowth over time of 
drug-resistant subclones will be quantified. These data should reveal the clonal evolution of ACC 
following tretinoin treatment over time and will define copy-number events that are associated with 
developing drug resistance.
We will use deep sequencing of cfDNA or CTCs to determine the changes of clonal composition in 


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30
ACC during tretinoin treatment. We plan to determine the somatic resistance mutations or other 
genetic aberrations in cfDNA and CTCs that occur following tretinoin treatment. To this end, we 
will perform next generation sequencing of DNA or RNA from CTCs or of cfDNA, and also of 
CD45+ cells from peripheral blood as matched controls. Somatic mutations can be determined using 
the Mutect algorithm [50], copy-number variations can be determined using Recapseq, and 
subclonality and cancer cell fraction of all mutations can be evaluated by the Absolute algorithm 
[51]. The concordance between cfDNA or CTCs and tumor tissue biopsies of ACC will be assessed 
for the time points detailed in the study calendar. Computational down sampling of these data will 
define the sequencing depth at which differences can be detected between cfDNA and tissue biopsy 
of ACC cells.
10. STUDY CALENDAR
Baseline evaluations are to be conducted within 28 days prior to study registration (except for 
pregnancy test and baseline tumor biopsy, as detailed below). If these screening assessments occur 3 
days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 values. Scans 
must be done within 28 days prior to study registration. 
As detailed in the Study Calendar, a negative pregnancy test in women of child-bearing potential 
must be documented within 72 hours before the first dose of study medication. 
A baseline tumor biopsy, obtained within 28 days before starting protocol therapy, is also required if 
tumor tissue is safely accessible. A second, on-treatment tumor biopsy sample will be obtained at the 
end of Cycle 2, within 14 days of Cycle 3 Day 1. A third (optional) biopsy will be performed if 
deemed safe or feasible at the time of confirmed disease progression (if that is the reason for coming 
off treatment). 
Baseline laboratory evaluations must be completed within 14 days prior to study registration. In the 
event that the participant’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours of treatment initiation of the next cycle of therapy. 
Assessments must be performed prior to administration of any study agent. Study assessments and 
agents should be administered within  3 days of the protocol-specified date, unless otherwise noted. 


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Protocol Version/Date: Original/February 23, 2019
31
ScreeningA
C1, D1
C2, D1
C2, 
D16-28
C3 and 
subsequent cycles
End of 
protocol 
Treatment 
VisitB
Post end of 
protocol 
treatment
TretinoinC
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X---------------------------------------------------------------------------X
Physical exam
X
X
X
X
X
Vital signs
X
X
X
X
X
Height
X
WeightD
X
X
X
X
X
Performance statusE
X
X
X
X
X
Hematology labs, 
coagulation profileF
X
X
X
X
X
Serum chemistries and 
lipid panelG
X
X
X
X
X
X
ECG
X
Tumor biopsyH
X
XH
XH
Research blood collectionI
X
X
XI
X
Adverse event evaluationJ
X---------------------------------------------------------------------------X
X
Tumor measurementsK
X
Tumor measurements are repeated every 8 weeks. Documentation 
(radiologic) must be provided for participants removed from study 
treatment for progressive disease.
XK
B-HCGL
XL
A. Baseline study evaluations are conducted within 28 days prior to study registration. If screening assessments are 3 days before 
the start of the start of study treatment, then they may serve as Cycle 1 Day 1 values. Baseline laboratory testing must be 
completed prior to 14 days of study registration.
B. The reason for protocol treatment removal and the date the participant was removed from protocol treatment must be 
documented in the study-specific case report form (CRF). Off protocol treatment visit is to occur within 30 days of final 
administration of study treatment. End of treatment assessments do not have to be repeated if the same assessments were 
performed within 7 days prior to the visit.
C. Tretinoin is dosed at 45 mg/m2/day divided into two daily doses for days 1 through 14 of a 28-day cycle (tretinoin will be held 
on days 15 through 28 of every cycle) until disease progression or unacceptable toxicity ensues in Cohort 1; tretinoin is dosed 
at 45 mg/m2/day divided into two daily doses continuously during a 28-day cycle until disease progression or unacceptable 
toxicity in Cohort 2. Following the first cycle of therapy, tretinoin cycles continue every 28 days or every 4-weeks. The pills 
should be taken with food (preferably with a fat-containing meal). Patients are required to complete a study drug diary and 
return the diary at the start of each Cycle (beginning with Cycle 2), and at the end of treatment.
D. Recorded in kilograms (kg) as the patient’s actual (not ideal or adjusted) body weight.
E. Using ECOG performance status scale of 0-5 (see Appendix A).
F. Hematology laboratory studies should include: CBC with differential and coagulation profile (PT/INR and aPTT).
G. Serum chemistries should include: a comprehensive metabolic panel with phosphorus and magnesium levels (as appropriate), 
and a non-fasting lipid panel to include a triglyceride, LDL, HDL, and total cholesterol values.
H. If tumor is accessible by surgical or percutaneous approach, a tumor biopsy should be performed at the following time points: 
(1) at baseline, within 28 days of Cycle 1 Day 1 of protocol therapy (ideally as close to administration of Cycle 1 Day 1 therapy 
as possible) but before the administration of the first dose of study treatment. (2) After cycle 2 (8 weeks on treatment), within 14 


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Protocol Version/Date: Original/February 23, 2019
32
days of the start of Cycle 3 Day 1 of protocol therapy – providing the procedure is considered safe, feasible, and accessible at 
the discretion of the treating investigator. (3) Patients may also be offered an optional end-of-treatment biopsy if the reason for 
discontinuation was progressive disease – again if safe and feasible.
I.
Research blood sample collections should occur at the following time points: (1) at baseline, within 14 days prior to Cycle 1 
Day 1 of protocol therapy (ideally as close to administration of Cycle 1 Day 1 therapy as possible), (2) at the beginning of every 
new Cycle, following C1 (expected to occur every 28-days) for the first 12 cycles or 1 year on treatment.
J.
Adverse event monitoring should utilize CTCAE version 5.0.
K. Radiographic evaluations should include contrast-enhanced CT imaging of the chest, abdomen, and pelvis; Contrast-enhanced 
MR imaging of the abdomen may replace CT abdomen and pelvis if further characterization of liver metastases is preferred (at 
the discretion of the treating physician). A neck CT with contrast should be obtained if appropriate: such as individuals with a 
history of ACC that arose in the head and neck, or with residual locoregional disease in the head and neck region. CT head or 
brain imaging is not required. PET-CT imaging can be considered in lieu of CT imaging at any given radiologic assessment, but 
both studies are often not required. Assessment will be made at baseline and participants will be followed for best overall 
response and development and documentation of first disease progression and for survival every 8 weeks throughout the course 
of the trial for 3 years from the time of study registration. Post end of protocol treatment, if first disease progression has not 
been documented, tumor assessments are to continue every 8 week until first disease progression. After first disease 
progression, patients will be followed every 8 weeks for survival (by phone) until death or 3 years from study registration 
(whichever occurs first). 
L. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 14 days of study  
registration. Female subjects of childbearing potential should have a negative urine or serum pregnancy test repeated within 72 
hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. Women who could potentially become pregnant while undergoing treatment on this 
protocol must be willing to use 2 methods of contraception.
11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 (not less than 4) weeks 
following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for target disease response.  These participants will 
have their response classified according to the definitions stated below.  (Note:  Participants 
who exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, absence, 
or unequivocal progression of the lesions. 


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11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray or ≥10 
mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-
measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same participant, these are preferred for selection as target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 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 (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 


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over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow 
up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  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 
the treatment.
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 unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 


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PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.  
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease.
11.1.4 Response Criteria
11.1.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study.
11.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm short 
axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 


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a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator).
11.1.4.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered.
11.1.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be


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            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.1.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) 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, or death 
due to any cause. Participants without events reported are censored at the last disease 
evaluation).
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
11.1.6 Survival and Clinical Parameters
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease evaluation.


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Time to Progression: Time to Progression (TTP) is defined as the time from randomization 
(or registration) to progression, or censored at date of last disease evaluation for those 
without progression reported.
Clinical benefit rate: defined as CR, PR and stable disease (SD) ≥ 24 weeks. 
11.1.7 Response Review
For trials where the response rate is the primary endpoint, it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the participants’ files and radiological images is the best approach. 
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. The committee is composed of medical oncologists, research nurses, 
pharmacists and biostatisticians with direct experience in cancer clinical research.  Information that 
raises any questions about participant safety will be addressed with the Overall PI and study team.
The DSMC will review each protocol up to four times a year with the frequency determined by the 
outcome of previous reviews. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 days 
of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while 
being treated and during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be provided upon 
request. 


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12.3
Multi-Center Guidelines
Not applicable.
12.4
Collaborative Agreements Language
Not applicable.
13. STATISTICAL CONSIDERATIONS
Original Design When Trial Opened.
The trial was originally designed as a two-stage one arm phase II trial with primary endpoint of best 
overall response with n=14 patients who are eligible and begin protocol treatment to be entered into 
the first stage. Details of the original design as follows:
The primary endpoint of this study is best overall response rate (CR+PR). A Simon two-stage design 
will be used to minimize the number of patients exposed to this regimen and the specific sample size 
and operating characteristics were chosen to be able to show that the response rate is greater than 
10% (that found in prior studies) and closer to 28%.  Fourteen eligible patients who start protocol 
treatment are to be accrued in the first stage. If there are ≤ 1 of 14 patients with disease in response, 
accrual to this trial will be closed with the expectation that there is little evidence that the response 
rate will reach 28%. The probability that the trial will close early is 58% if the true response rate is 
10%. If there are >1 patients with disease in response, accrual will continue until a total of 25 
eligible patients who start protocol treatment are entered. If > 4 of 25 patients who are eligible and 
begin protocol treatment have disease in response, then this regimen will  be considered worth 
further study. The probability of concluding that the regimen is worth further study is 85% if the true 
response rate is 28%. The probability of concluding that the regimen is worth further study is 9% if 
the true response rate is 10%. Allowing 2 patients to be entered and then declared ineligible and/or to 
not start protocol treatment, the overall accrual goal is 27. 
Amendment 3: Details, Rational and Design:
Fourteen patients (eligible and began protocol streatment) have been entered into stage 1 for the 
original design when the trial opened and now referred to as ‘Cohort 1’.  Due to preliminary results 
of low efficacy in Cohort 1, accrual to Cohort 1 is suspended and n=6 additional patients (‘Cohort 
2’) are to be entered to assess safety and tolerability of continuous daily dosing. The choice of n=6 is 
due to lack of concerning SAEs in Cohort 1 as well as to keep within the constraints of original 
budget and its corresponding drug availability for the testing of continuous dosing. For Cohort 2, 
AEs plan to be continuously monitored and best overall response assessed. Cohort 2 is a secondary 
endpoint to assess safety and tolerability of continuous daily dosing in an additional 6 subjects. With 
n=6 eligible patients who being protocol treatment, the lower limit of one-sided 90% exact 
binomial confidence interval will be greater than 10% (the null hypothesis in the original 
design) if at least 3 patients have disease in response (CR or PR). All aspects of the AE profile 
and outcome of these 6 patients are to be assessed with decisions made regarding amending the 
trial for any further design changes and continuation or closure of accrual. The table below 
gives the lower limit of one-sided 90% exact binomial confidence interval based on various 


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scenarios.
Sample 
size 
Cohort 2
# of patients with 
disease in response
Lower limit of one-
sided 90% CI
6
2
9.2%
6
3
20.1%
 
Analysis and Accrual Estimates
The primary efficacy population includes all eligible patients who begin protocol treatment. Best 
overall response will be summarized as a proportion with a corresponding exact 95% confidence 
interval (CI). 
For secondary objectives: 
• Adverse events will be classified and graded according to the CTCAE v.5.0. Frequencies of 
adverse events will be summarized among patients who begin protocol therapy. 
• The distributions of time-to-event endpoints will be estimated using the Kaplan-Meier 
method with corresponding 95% confidence intervals for the median or time-specific event 
time. 
With an estimated monthly accrual of 2 patients, accrual to the first stage (Cohort 1) is estimated to 
take approximately 7-8 months to accrue n = 15 (of which n = 14 who are eligible and who begin 
protocol treatment).  Estimated monthly accrual to Cohort 2 is estimated to be similar (1-2 patients 
per month). Due to possible delays in initiation of approval and/or in initiation of accrual itself, 
accrual could take longer.  As is customary with this type of design, accrual will be suspended after 
the first stage (Cohort 1, n = 14 eligible patients who begin protocol therapy) in order to assess 
outcome; however, this suspension is also dependent on the actual observed accrual rate and the 
number of patients with confirmation of disease response status while the first stage of the trial is 
accruing. Accrual to Cohort 2 would be suspended when n=6 eligible patients who begin protocol 
therapy are entered.
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of the 
study is the time point at which the last data items are to be reported, or after the outcome data are 
sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study 
Duration (Section 13.0). If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) 
years after the end of the study. The overall study PI will be responsible for reporting and publishing 
the data.


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15. REFERENCES
1.
Bobbio A, C.C., Ampollini L, Bianchi B, Carbognani P, Bettati S, Sesenna E, Rusca M, Lung 
metastasis resection of adenoid cystic carcinoma of salivary glands. Eur J Cardiothorac Surg, 
2008. 33(5): p. 790-3.
2.
Spiro RH, H.A., Strong EW., Adenoid cystic carcinoma of salivary origin. A 
clinicopathologic study of 242 cases. Am J Surg, 1974. 128(4): p. 512-20.
3.
Amini A, W.T., Brower JV, Jones BL, McDermott JD, Raben D, Ghosh D, Bowles DW, 
Karam SD, Association of Adjuvant Chemoradiotherapy vs Radiotherapy Alone With 
Survival in Patients With Resected Major Salivary Gland Carcinoma: Data From the 
National Cancer Data Base. JAMA Otolaryngol Head Neck Surg, 2016. 142(11): p. 1100-
10.
4.
Gao M, H.Y., Huang MX, Ma DQ, Luo HY, Gao Y, Peng X, Yu GY Clinicopathological 
study of distant metastases of salivary adenoid cystic carcinoma. Int J Oral Maxillofac Surg, 
2013. 42(8): p. 923-8.
5.
Laurie SA, H.A., Fury MG, Sherman E, Pfister DG, Systemic therapy in the management of 
metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic 
review. Lancet Oncol, 2011. 12(8): p. 815-24.
6.
Airoldi M, P.F., Succo G, Gabriele AM, Ragona R, Marchionatti S, Bumma C, Phase II 
randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with 
recurrent salivary gland malignancies. Cancer, 2001. 91(3): p. 541-7.
7.
Licitra L, C.R., Grandi C, Palma SD, Guzzo M, Demicheli R, Molinari R, Cisplatin, 
doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial 
of 22 patients. Ann Oncol, 1996. 7(6): p. 640-2.
8.
Sridharan V, G.E., Liao X, Chau NG, Haddad RI, Severgnini M, Hammerman P, El-Naggar 
A, Freeman GJ, Hodi FS, Rodig SJ, Dranoff G, Schoenfeld JD, Immune Profiling of Adenoid 
Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating 
Lymphocytes. Cancer Immunol Res, 2016. 4(8): p. 679-87.
9.
Cohen RB, D.J., Doi T, Piha-Paul SA, Liu SV, Gilbert J, Algazi AP, Damian S, Hong RL, Le 
Tourneau C, Day D, Varga A, Elez E, Wallmark J, Saraf S, Thanigaimani P, Cheng J, Keam 
B, Pembrolizumab for the Treatment of Advanced Salivary Gland Carcinoma: Findings of 
the Phase 1b KEYNOTE-028 Study. Am J Clin Oncol, 2018. Feb 21. doi: 
10.1097/COC.0000000000000429. [Epub ahead of print].
10.
Hotte SJ, W.E., Lamont E, MacKenzie M, Vokes E, Chen EX, Brown S, Pond GR, Murgo A, 
Siu LL, Imatinib mesylate in patients with adenoid cystic cancers of the salivary glands 
expressing c-kit: a Princess Margaret Hospital phase II consortium study. J Clin Oncol, 
2005. 23(3): p. 585-90.
11.
Thomson DJ, S.P., Denton K, Bonington S, Mak SK, Swindell R, Homer J, Sykes AJ, Lee 
LW, Yap BK, Slevin NJ, Phase II trial of sorafenib in advanced salivary adenoid cystic 
carcinoma of the head and neck. Head Neck, 2015. 37(2): p. 182-7.
12.
Wong SJ, K.T., Hayes DN, Kies MS, Cullen KJ, Tanvetyanon T, Argiris A, Takebe N, Lim 
D, Saba NF, Worden FP, Gilbert J, Lenz HJ, Razak AR, Roberts JD, Vokes EE, Cohen EE, 
Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic 
carcinoma and for nonadenoid cystic malignant salivary tumors. Ann Oncol, 2016. 27(2): p. 
318-23.
13.
Ho AS, K.K., Roy DM, Morris LG, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, 


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Huse JT, Zhang J, Dolgalev I, Huberman K, Heguy A, Viale A, Drobnjak M, Leversha MA, 
Rice CE, Singh B, Iyer NG, Leemans CR, Bloemena E, Ferris RL, Seethala RR, Gross BE, 
Liang Y, Sinha R, Peng L, Raphael BJ, Turcan S, Gong Y, Schultz N, Kim S, Chiosea S, 
Shah JP, Sander C, Lee W, Chan TA, The mutational landscape of adenoid cystic carcinoma. 
Nat Genet, 2013. 45(7): p. 791-8.
14.
Persson M, A.Y., Moskaluk CA, Frierson HF Jr, Cooke SL, Futreal PA, Kling T, Nelander S, 
Nordkvist A, Persson F, Stenman G, Clinically significant copy number alterations and 
complex rearrangements of MYB and NFIB in head and neck adenoid cystic carcinoma. 
Genes Chromosomes Cancer, 2012. 51(8): p. 805-17.


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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B
INFORMATION ON POSSIBLE DRUG INTERACTIONS TRETINOIN
Drugs that may interact with tretinoin 

Anti-seizure medications such as carbamazepine, phenobarbital, phenytoin, primidone 

Arthritis medications such as leflunomide, tofacitinib 

Some oral contraceptives 

Some antibiotics, like doxycycline, tetracycline, and tigecycline 

Other medications such as aminolevulinic acid, amiodarone, clopidogrel, deferasirox, gemfibrozil, 
irbesartan, losartan, mifepristone, natalizumab, pioglitazone, rabeprazole, rifampin, ritonavir, 
rosiglitazone, tranexamic acid 
Food and supplements that may interact with tretinoin** 

Echinacea 

St. John’s Wort 

Vitamin A supplements or multivitamins that contain vitamin A 
** Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All 
forms should be avoided. 


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APPENDIX C                  TRETINOIN DOSING TABLE 
Example Tretinoin Dosing Table
BSA (m2)
Dose
 0.78
20 mg in the AM, 10 mg in the PM
0.79 – 0.99
20 mg twice daily
1 – 1.22
30 mg in the AM, 20 mg in the PM
1.23 – 1.44
30 mg twice daily
1.45 – 1.66
40 mg in the AM, 30 mg in the PM
1.67 – 1.88
40 mg twice daily
1.89 – 2.11
50 mg in the AM, 40 mg in the PM
2.12 – 2.33
50 mg twice daily
2.34 – 2.55
60 mg in the AM, 50 mg in the PM
2.56 – 2.77
60 mg twice daily
2.78 – 2.99
70 mg in the AM, 60 mg in the PM
3 – 3.22
70 mg twice daily
3.23 – 3.44
80 mg in the AM, 70 mg in the PM
 3.45
80 mg twice daily
Note: The higher dose of an uneven dose will be the AM or morning dose.
For additional administration guidelines for administering tretinoin to patients unable to swallow 
whole capsules either due to young age or level of consciousness (including intubated patients) 
please 
see 
Appendix 
D. 
Further 
details 
about 
tretinoin 
can 
also 
be 
found 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20438s004lbl.pdf 


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APPENDIX D               INFORMATION FOR PARENTS/CAREGIVERS FOR GIVING TRETINOIN
Tretinoin (ATRA) gel capsules should be swallowed whole when possible. There is minimal data on 
the absorption of tretinoin when it is given by other methods. In addition, tretinoin is sensitive to 
heat, light and air, so avoid exposure to those as much as possible. Alternative methods of delivery 
should only be used when it is not possible to swallow the gel capsules (i.e., intubated patients, 
neurologically impaired patients, very young patients).
Note: Gloves must be worn when handling tretinoin capsules unless the capsules are intact.
For patients unable to swallow the capsules whole, the following options may be used:
1. Capsules can be chewed then swallowed if the patient is able. A small hole can be poked 
in the capsules before the patient chews them to make this easier.
2. Capsules can be softened in water and the softened capsule can be chewed/swallowed 
and/or mixed with pudding or a fatty food and swallowed.
3. Contents of the capsules can be squeezed out and mixed with a fatty food. If at all 
possible, have the patient suck on the empty capsule in hopes of getting more of the 
intended dose.
4. If the contents are withdrawn from the capsules and mixed with food, give the dose as 
soon as possible (within ONE hour).


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
47
APPENDIX E
REQUIRED SPECIMENS, PROCESSING AND SHIPMENT 
INSTRUCTIONS FOR BIOMARKER, CORRELATIVE AND SPECIAL STUDIES
Peripheral Blood Samples
Specimens will be shipped (via overnight air FEDEX traceable carrier) to and subsequently 
processed and analyzed at Dana-Farber Cancer Institute. Participating sites are responsible for 
maintaining a log of all biospecimen and for shipment of bone marrow specimens. An inventory 
sheet and shipping manifest must accompany each shipment and copies provided to the Coordinating 
Center. 
Participating sites are responsible for shipment of peripheral blood specimens. An initial shipment of 
collection tubes will be shipped to all DF/HCC and non-DF/HCC participating sites at the time of 
site initiation.  Refill supplies may be requested by contacting the Coordinating Center.  
Specimens required per participant per time point: 

2 purple top tubes (EDTA), 10 mL each 

1 Streck Cell-Free DNA BCT tube, 10 ml
Specimens must be collected on Mondays, Tuesdays, Wednesdays or Thursdays for same-day 
shipment (FEDEX). All tubes (purple to and green top) should be shipped with a fridge pack Fed-Ex 
priority overnight. 
Blood samples will be collected at the time points outlined in the study calendar:
Documenting Instructions: Sites must maintain a detailed log of all samples obtained, including:
o
Subject Initials
o
Subject study ID
o
Type of sample
o
Visit at which sample was drawn (Screening, Cycle number and day, End of study 
treatment or Follow-Up)
o
Date sample drawn (mm/dd/yyyy)
o
Time sample drawn (24 hour clock)
o
Date Shipped
Processing Information: There is no required processing for blood samples at each participating 
site prior to shipment.
Shipping Instructions: Shipments must be sent on the day of collection and cannot be batched.

Label all specimens with the following:
o
Protocol Number
o
Subject Initials
o
Subject study number
o
Visit at which sample was drawn (Screening, Cycle number and day, End of study 
treatment or Follow-Up)


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
48
o
Date sample drawn (mm/dd/yyyy)
o
Time sample drawn (24 hour clock)

An inventory sheet including a complete list of samples shipped (patient number, time point, 
study #) must accompany each shipment. Please sign and date the form, and retain a copy for 
site record maintenance. Please see form in Appendix.

An electronic copy of the sample list (Appendix) and a copy of the shipping manifest must 
also be sent via email or fax to the Coordinating Center.  The listing must also include a 
contact name, address and phone number of the person who is responsible for the 
shipment. Please email the Coordinating Center to notify of an incoming shipment.  

Please ship Monday, Tuesday, Wednesday or Thursday as shipments cannot be received on 
weekends and/or on holidays.

Once drawn, samples should be shipped with a fridge pack Fed-Ex priority overnight to 
Dana-Farber Cancer Institute attention:
Jens G. Lohr, M.D., Ph.D.
Dana-Farber Cancer Institute
Dana-Building 542
450 Brookline Avenue
Boston, MA 02215
Email: JLOHR@partners.org 
Phone: 617-632-2069 or 415-816-8405


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
49
APPENDIX F 
STUDY PARTICIPANT SELF-ADMINISTRATION INSTRUCTIONS
Study Participant Self‐Administration Instructions 
The study staff will explain how to take the study drug TRETINOIN but these are points to 
remember: 

Tretinoin capsules should be swallowed whole 

Tretinoin is sensitive to heat, light, and air so avoid exposure as much as possible 

Take tretinoin with food 

Please call your doctor or research nurse before taking any new prescription or over‐ 
the‐counter medications/supplements other than the study drugs. 

For patients unable to swallow the capsules whole, the following options may be used:
o
Capsules can be chewed then swallowed if the patient is able. A small hole can be 
poked in the capsules before the patient chews them to make this easier. 
o
Capsules can be softened in water and the softened capsule can be chewed/swallowed 
and/or mixed with pudding or a fatty food and swallowed.
o
Contents of the capsules can be squeezed out and mixed with a fatty food. If at all 
possible, have the patient suck on the empty capsule in hopes of getting more of the 
intended dose. 
NOTE: If the contents are withdrawn from the capsules and mixed with food, give the dose as soon 
as possible (within ONE hour). 
SUMMARY OF CHANGES
Date
Change
12/31/2019 Amendment 2
Addition of cohort 2 throughout the protocol. 
Fasting is no longer required for the lipid panel.


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
50


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
51
Study Participant Self‐Administration Study Drug Diary 
Please record how many capsules you take of TRETINOIN, the time you take them and any 
comments here below and bring the completed diary as well as your study drug supply, including 
empty bottles, to every study visit. This will help us keep track of your study drug and how well you 
are tolerating it. 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
52
Day 
Date 
Number of 
Tretinoin 
Capsules 
Time of Dose 
Number of 
Tretinoin 
Capsules 
Time of Dose 
1 / 15
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
2 / 16
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
3 / 17
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
4 / 18
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
5 / 19
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
6 / 20
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
7 / 21
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
8 / 22
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
9 / 23
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
10 / 24
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
11 / 25
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
12 / 26
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
13 / 27
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
14 / 28
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
______:______ □ a.m. / □ p.m. □ Dose Not Taken 
Why:________________________ 
Participant/Caregiver Signature: _______________________________ Date: _________________ 


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
53


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
54


NCI Protocol #: TBD
DF/HCC Protocol #: 19-224
Protocol Version/Date: Original/February 23, 2019
55