Conditions: Unresectable Intrahepatic Cholangiocarcinoma
Keywords: colony stimulating factor -1 receptor (CSF-1R) inhibitor Anti-PD-1 (receptor blocking antibody) Immunotherapy Intra-arterial therapy Y90 (yttrium-90 radioembolization) conventional transarterial chemoembolization (cTACE) Chemo-embolization Radio-embolization Biliary tract Intrahepatic Cholangiocarcinoma Monoclonal antibody
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purposed of this research is to study the safety and clinical activity of the combination of durvalumab and a CSF-1R inhibitor (SNDX-6352) in people with Intrahepatic Cholangiocarcinoma.

Detailed description:

Arms:
arm 1: Participants will receive Durvalumab and SNDX-6352.

Interventions: intervention 1: Durvalumab intervention 2: SNDX-6352
Intervention descriptions: intervention 1: 1. Durvalumab - 1500 mg via IV infusion over 60 minutes (-5/+10 min) on day 1 of each 28-day cycle (every 4 weeks).
2. Drug - 1500mg IV intervention 2: 1. SNDX-6352 - 3mg/kg via IV infusion over 30 minutes (-5/+10 min) on days 1 and 15 of each 28-day cycle (every 2 weeks), starting with cycle 2 (not given during cycle 1).
2. Drug - 3mg/kg IV

Protocol document:
Prot_SAP_000.pdf: 


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Version 1.2 / April 7, 2020 
Version 1.3 / April 24, 2020 
Version 1.4 / October 21, 2020 
Version 2.0 / March 4, 2021 
Version 3.0 / February 7, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SCHEMA ...........................................................................................................................................2 
1. 
OBJECTIVES .......................................................................................................................5 
1.1. 
Primary Objectives ......................................................................................................5 
1.2. 
Secondary Objectives ..................................................................................................5 
1.3. 
Exploratory Objective .................................................................................................5 
1.4. 
Primary Endpoint ........................................................................................................5 
1.5. 
Secondary Endpoints ..................................................................................................6 
1.6. 
Exploratory study endpoints .......................................................................................6 
1.7. 
Study Design ...............................................................................................................6 
2. 
BACKGROUND ...................................................................................................................7 
2.1. 
Disease Type ...............................................................................................................7 
2.2. 
Anti-PD-1/PD-L1 blockade (Durvalumab [IMFINZI]) ..............................................7 
2.3. 
CSF-1R Inhibition (SNDX-6352) ...............................................................................8 
2.4. 
Preclinical and Clinical Trial Data ..............................................................................8 
2.5. 
Rationale .....................................................................................................................8 
2.6. 
Potential risks of durvalumab and SNDX-6352 .........................................................9 
2.7. 
Rationale for fixed dosing durvalumab .....................................................................11 
3. 
PATIENT SELECTION ....................................................................................................12 
3.1. 
Eligibility Criteria for enrollment into study ............................................................12 
3.2. 
Exclusion Criteria .....................................................................................................13 
3.3. 
Inclusion of Women and Minorities .........................................................................16 
4. 
TREATMENT PLAN .........................................................................................................16 
4.1. 
Agent Administration ................................................................................................16 
4.2. 
General Concomitant Medication and Supportive Care Guidelines .........................18 
4.3. 
Definition of an Overdose for this Protocol ..............................................................22 
4.4. 
Contraception, Use in Pregnancy, Use in Nursing ...................................................22 
4.5. 
Unacceptable Toxicities ............................................................................................24 
4.6. 
Criteria for Removal from Study Treatment .............................................................26 
4.7. 
Off Study/Safety Follow-up Visit .............................................................................26 
4.8. 
Duration of Follow Up ..............................................................................................27 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................27 
5.1. 
Dose Modifications ...................................................................................................27 
5.2. 
Dosing Delays ...........................................................................................................27 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .........................28 
6.1. 
Definitions.................................................................................................................28 
6.2. 
Relationship ..............................................................................................................31 
6.3. 
Grading .....................................................................................................................32 
6.4. 
Expectedness .............................................................................................................32 
6.5. 
Handling of Expedited Safety Reports .....................................................................32 
6.6. 
Reporting...................................................................................................................33 
7. 
PHARMACEUTICAL INFORMATION .........................................................................37 
7.1. 
Durvalumab (IMFINZI) ............................................................................................37 


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7.2. 
SNDX-6352 ..............................................................................................................39 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................41 
8.1. 
Tumor and Immune Biology Correlative Studies .....................................................41 
8.2. 
Diagnostic Tissue Samples .......................................................................................42 
9. 
STUDY SCHEDULE ..........................................................................................................43 
10. 
MEASUREMENT OF EFFECT .......................................................................................45 
10.1. Definitions.................................................................................................................45 
10.2. Methods for Evaluation of Measurable Disease .......................................................45 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ........................................46 
11.1. Data Management .....................................................................................................46 
11.2. Safety Meetings ........................................................................................................46 
11.3. Monitoring ................................................................................................................46 
12. 
STATISTICAL CONSIDERATIONS ..............................................................................46 
12.1. Sample Size ...............................................................................................................46 
12.2. Primary Analysis .......................................................................................................47 
12.3. Safety monitoring plan ..............................................................................................48 
12.4. Analysis of Immune Measurements..........................................................................48 
13. 
REFERENCES ....................................................................................................................49 
 
APPENDIX A: Performance Status Criteria .................................................................. 51 
APPENDIX B: Adverse Event of Clinical Interest (ECI) Reporting Form ................. 52 
APPENDIX C: SAE Reporting Form .............................................................................. 54 
APPENDIX D: mRECIST Criteria .................................................................................. 56 
APPENDIX E: Dosing Modification and Toxicity Management Guidelines ............... 58 


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1. OBJECTIVES 
 
1.1. Primary Objectives 
 
1.1.1. To assess the objective response rate (ORR) in patients with intrahepatic 
cholangiocarcinoma receiving combination therapy with durvalumab and a CSF-1R 
inhibitor (SNDX-6352) after receiving intra-arterial therapy (IAT).  
 
1.1.2. To determine the safety and feasibility of combination therapy with durvalumab and 
a CSF-1R inhibitor (SNDX-6352) in patients after receiving intra-arterial therapy 
(IAT). 
 
1.2. Secondary Objectives  
 
1.2.1. To determine the overall survival (OS) of patients with intrahepatic 
cholangiocarcinoma receiving combination therapy with durvalumab and a CSF-1R 
inhibitor (SNDX-6352) after receiving intra-arterial therapy (IAT). 
 
1.2.2. To determine the progression-free survival (PFS) of patients with intrahepatic 
cholangiocarcinoma receiving combination therapy with durvalumab and a CSF-1R 
inhibitor (SNDX-6352) after receiving intra-arterial therapy (IAT).  
 
1.2.3. To determine duration of response of patients with intrahepatic cholangiocarcinoma 
receiving combination therapy with durvalumab and a CSF-1R inhibitor (SNDX-
6352) after receiving intra-arterial therapy (IAT). 
 
1.3. Exploratory Objective 
 
1.3.1. To assess correlative immunologic parameters in biopsy specimens, including PD-
L1 expression.  
 
1.3.2. To explore potential molecular determinants of response, progression, and disease 
stability using next generation sequencing and other sequencing techniques 
 
1.4. Primary Endpoint 
 
 
1.4.1. Efficacy Endpoint  
• To assess object response using mRECIST criteria for patients receiving IAT 
followed by durvalumab/SNDX-6352 
 
1.4.2. Safety Endpoints 
• Grade 3 or higher toxicities according to National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAE; Version 5.0)  
• Incidence, nature and severity of all adverse events  
 
 
 


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1.5. Secondary Endpoints   
 
1.5.1. Efficacy Endpoints 
• Progression-free 
survival 
(PFS) 
of 
patients 
with 
intrahepatic 
cholangiocarcinoma receiving combination therapy with durvalumab and a 
CSF-1R inhibitor (SNDX-6352) after receiving intra-arterial therapy (IAT), 
defined as the time from the start of IAT until first documented evidence of 
disease recurrence or death. 
• OS, defined as the time from the start of IAT until death from any cause. 
• Duration of response among the patients who have objective response. 
 
1.6. Exploratory study endpoints 
 
1.6.1. Correlative Endpoints 
• Granzyme B+ CD8 T cells. The change of Granzyme B+ CD8 T cells after 
single agent durvalumab vs after combination durvalumab/SNDX-6352 from 
the same patients, and the change compared to pretreatment biopsy of the same 
patient as the baseline. 
• IHC, flow cytometry, quantitative PCR assays, microarray analysis, and next 
generation sequencing compared between pre- and post-treatment tumor 
specimens and research blood samples 
• To assess correlation between immune parameters and clinical outcomes  
 
1.7. Study Design  
 
This is an open-label, single institution, single arm study of the combination of durvalumab and 
SNDX-6352 (axatilimab) in patients with intrahepatic cholangiocarcinoma undergoing intra-
arterial therapy.  
Up to 30 patients with unresectable intrahepatic cholangiocarcinoma will be selected to receive 
either trans-arterial chemo-embolization (cTACE) or radio-embolization (Y90) per defined criteria 
based on tumor size and location. A core biopsy will be performed at the beginning of this intra-
arterial therapy (IAT) procedure. Immunotherapy will start one week following the first IAT 
procedure. During the first 28-day cycle of immunotherapy, durvalumab will be given on Day 1 
as a single agent treatment. After cycle 1, a post-durvalumab single agent research biopsy will be 
performed. Beginning with the second cycle, durvalumab and SNDX-6352 combination therapy 
will be given on Day 1 (both drugs) and Day 15 (SNDX-6352 only) of each 28 day cycle.  After 
cycle 2 (the first cycle during which patients will receive combination therapy), a post-
durvalumab/SNDX-6352 research biopsy will be performed at the start of the second IAT 
procedure. After the second IAT procedure, additional cycles of durvalumab and SNDX-6352 
combination therapy will be administered until disease progression.  
 
Liver MRI will be performed before the first IAT (at screening) and before the second IAT (week 
9). CT chest/abdomen/pelvis will be performed at screening, before the second IAT (week 9), prior 
to Cycle 5 immunotherapy (week 18), and approximately every 8 weeks thereafter to assess disease 
progression per mRECIST criteria. Patients may continue the immunotherapy if CT or MRI shows 
local progression until two IATs have been performed.  After the second IAT, the patient will be 
taken off the study if local progression is confirmed at a subsequent scan or if any extrahepatic 


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disease progression has occurred.  Objective response will be assessed as the best overall response 
during the study.   
 
2. BACKGROUND 
 
2.1. Disease Type 
 
Cancer in the liver, both encompassing primary and metastatic liver carcinoma is one of the most 
prevalent malignancies.  Biliary tract cancers (BTC) broadly includes tumors of the gallbladder, 
intrahepatic bile ducts (ICC), extrahepatic bile ducts, perihilar/distal bile ducts, and the ampulla of 
Vater have dismal 5 year survival rates ranging from 5-15%1,2.  Of the nearly 10,000 diagnoses of 
BTC in the US annually, the majority present as advanced disease that is managed with intra-
arterial therapy (IAT), including chemo- and radio-embolization as well as systemic 
chemotherapy3.  ICC comprises 10-15% of worldwide primary liver malignancies and is the 
second most common primary liver malignancy after hepatocellular carcinoma (HCC) with 
varying worldwide incidence.  In recent years, global incidence has been increasing4.  SBRT is 
being increasingly utilized in management of BTC.  Median overall survival after liver directed 
therapy is approximately 13.2 months5.  Response rates in small studies with Y90 have been 
reported ranging from 12- 27%. The response rates from TACE have been challenging to compare 
since tumor necrosis is often reported as a response. However response rates have been reported 
ranging from 8.7-37%.  Our group previously reported a retrospective analysis of 198 ICC patients 
who received IAT, including conventional transarterial chemoembolization (cTACE) (64.7%), 
drug-eluting beads (DEB) (5.6%), bland embolization (TAE) (6.6%), or yttrium-90 radio 
embolization (23.2%)5.  The outcomes of this study will be compared to this historical control. In 
this historical control cohort, assessment of tumor response revealed complete or partial response 
in 25.5% patients, while 61.5% had stable disease; 13.0% had progressive disease. Furthermore, 
systemic therapy for advanced disease is not extremely effective.  Standard first-line systemic 
chemotherapy (cisplatin and gemcitabine) provides median PFS and OS of 8.0 and 11.7 months, 
respectively6.  Thus a better therapeutic strategy is necessary.  
 
2.2. Anti-PD-1/PD-L1 blockade (Durvalumab [IMFINZI]) 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation is not a new concept7. Evidence demonstrates a relationship between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies.  
Specifically, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term survival in solid 
malignancies such as ovarian, colorectal and pancreatic cancer, hepatocellular carcinoma, 
malignant MEL and RCC.  TILs can be expanded ex vivo and re-infused, inducing durable 
objective tumor responses in cancers such as melanoma8,9.  
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in various tumors10-13.  Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 


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detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments.  PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas 
PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues12.  High expression of 
PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor 
prognosis and survival in various cancer types, including renal cell carcinoma (RCC),14 pancreatic 
carcinoma,15 hepatocellular carcinoma,16 and ovarian carcinoma17.  Furthermore, PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with malignant melanoma18.  
Clear correlation between PD-L1 expression in many solid malignancies with minimal expression 
in normal tissue suggests PD-L1 may be an efficacious target for anti-cancer therapy. 
2.3. CSF-1R Inhibition (SNDX-6352) 
 
SNDX-6352 is a humanized IgG4 monoclonal antibody (mAb) with high affinity against colony 
stimulating factor-1 receptor (CSF-1R) and is being developed for the treatment of neoplastic 
diseases. CSF-1R is expressed on cells of the mononuclear phagocyte lineage including 
immunosuppressive macrophages that accumulate within the tumor microenvironment. These 
tumor-associated macrophages (TAMs) are believed to play a key role in inhibiting anti-tumor T-
cell immune responses while promoting tumor progression. High levels of TAMs have been shown 
to correlate with poor prognosis for certain cancers and preclinical studies have demonstrated that 
inhibition of TAMs can enhance anti-tumor immune responses. By binding to CSF-1R and 
blocking activation by its two known ligands, colony stimulating factor-1 (CSF-1) and interleukin-
34 (IL-34), SNDX-6352 can affect the migration, proliferation, differentiation, and survival of 
TAMs. By targeting this key cellular player in the pathogenesis of cancer, SNDX-6352 has the 
potential to slow disease progression and increase the clinical benefit of anti-tumor 
immunotherapeutic approaches. 
 
2.4. Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure [IB] for Preclinical and Clinical Data 
 
2.5. Rationale 
Systemic therapy targeting the immune system has had unprecedented success in solid tumors 
previously regarded as non-immunogenic, for example lung cancer19.  Activated T cells can be 
functionally inactivated in tumor tissue by engagement of the programmed cell death 1 (PD-1) 
receptor with its ligand (PD-L1)20.  PD-L1/PD-1 functions as a checkpoint which regulates the 
effector phase of T cell responses21.  The degree of somatic mutations or “mutational burden” in 
solid tumors has been associated with response to immunotherapeutic agents.   In non-small lung 
cancer, this association results in improved objective response, durable clinical benefit and 
improved PFS with anti-PD-1 therapy22.  In addition, PD-L1 expression had been found to be 
upregulated in this specific subcategory of BTC23.   
For 
hepatobiliary 
cancers, 
IAT, 
through 
DNA 
damaging 
chemoembolization 
and 
radioembolization, is anticipated to generate more somatic mutations in the liver cancer cells and 
potentially induce neoantigens.  Colony-stimulating factor 1(CSF-1) and its receptor CSF-1R 
regulate the migration, differentiation, and survival of macrophages24.  In solid tumors, tumor-
associated macrophages (TAM) secrete growth factors which release immunosuppressive 
cytokines which promote tumor growth and are associated with poor prognosis25.  CSF-1R 


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inhibition in combination with chemotherapy in preclinical models has been shown to result in 
increased CD8+ T cells, TAM-derived interleukin-10 (IL-10) production and a reduction in tumor 
burden26.  CSF-1R inhibition alone rarely produces a potent anti-tumor response but there is 
emerging evidence that CSF/CSF-1R blockade can reprogram TAMs and render tumors more 
susceptible to PD-L1/PD-1 blockade27. 
In vitro binding studies showed that SNDX-6352 is able to bind recombinant and native, cell 
expressed human CSF-1R. Cross-reactivity to cynomolgus monkey CSF-1R was demonstrated by 
flow cytometric analysis of monocytes and in protein binding experiments using BIAcore 
technology. The affinity was shown to be similar to human CSF-1R. Functional in vitro assays 
based upon the release of monocyte chemoattractant protein-1 (MCP-1) following stimulation of 
primary monocytes showed that SNDX-6352 was equipotent in both human and cynomolgus 
monkeys. 
 
Hepatobiliary cancers are abundantly infiltrated with macrophages and M2-tumor associated 
macrophages (TAM) is associated with the risk of developing metastasis28,29.   SNDX-6352 is a 
human IgG4 monoclonal antibody designed to target the CSF-1R. By binding to CSF-1R and 
blocking activation by its two known ligands, colony stimulating factor-1 (CSF-1) and interleukin-
34 (IL-34), SNDX-6352 can affect the migration, proliferation, differentiation, and survival of 
TAMs. A phase 1 dose escalation study of SNDX-6352 has been conducted in patients with 
unresectable, recurrent locally-advanced or metastatic solid tumors and the recommended Phase 2 
dose (RP2D is 3 mg/kg every 2 weeks (Q2W).  
 
2.6. Potential risks of durvalumab and SNDX-6352 
 
2.6.1. Overall Risks 
 
Monoclonal antibodies directed against immune checkpoint proteins, such as programmed 
cell death ligand 1 (PD-L1) as well as those directed against programmed cell death-1 (PD-
1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), aim to boost endogenous immune 
responses directed against tumor cells. By stimulating the immune system however, there is 
the potential for adverse effects on other tissues. Most adverse drug reactions seen with the 
immune checkpoint inhibitor class of agents are thought to be due to the effects of 
inflammatory cells on specific tissues. These risks are generally events with a potential 
inflammatory or immune mediated mechanism and which may require more frequent 
monitoring and/or unique interventions such as immunosuppressants and/or endocrine 
therapy. These immune mediated effects, can occur in nearly any organ system, and are most 
commonly seen as gastrointestinal AEs such as colitis and diarrhea, pneumonitis/interstitial 
lung disease (ILD), hepatic AEs such as hepatitis and liver enzyme elevations, skin events 
such as rash and dermatitis and endocrinopathies including hypo- and hyper-thyroidism. 
2.6.2. Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes 
mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in transaminases, 
nephritis/increases 
in 
creatinine, 
pancreatitis/increases 
in 
amylase 
and 
lipase, 
rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare or less frequent 






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3. PATIENT SELECTION 
 
3.1. Eligibility Criteria for enrollment into study  
 
3.1.1. Have cytologically confirmed intrahepatic cholangiocarcinoma. 
 
3.1.2. All disease must be localized to the liver (locally advanced). 
 
3.1.3. Be a candidate for conventional transarterial chemoembolization or yttrium-90 
radioembolization, the two most common modalities of IAT. 
 
3.1.4. Have measurable disease by mRECIST. Measurable disease will be confirmed by 
radiological imaging (MRI, CT).  
 
3.1.5. Age >18 years at time of study entry. 
 
3.1.6. Body weight > 30 kg.  
3.1.7. ECOG (World Health Organization) performance status 0-1 (Appendix A) 
 
3.1.8. Life expectancy ≥12 weeks. 
 
3.1.9. Adequate normal organ and marrow function as defined below: 
• Absolute neutrophil count 
> 1,500 cells/mm3 
• Hemoglobin 
> 8 g/dL 
• Platelets 
> 100,000 cells/mm3 
• Serum creatinine 
< 1.5 x ULN 
• AST and ALT  
< 2 x ULN 
• Total bilirubin 
≤ 1.5 x ULN** 
• PT or INR 
≤ 1.5 x ULN 
• Albumin 
> 2.8 g/dL 
• Child Pugh Class A 
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine 
clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 
1976) or by 24-hour urine collection for determination of creatinine clearance: 
Males: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
   
72 x serum creatinine (mg/dL) 
 
Females: 
Creatinine CL 
(mL/min) 
= 
Weight (kg) x (140 – Age) 
  x 0.85 
72 x serum creatinine (mg/dL) 
 
**Subjects with Gilbert’s Syndrome should have direct bilirubin within 
normal institutional limits. 
 


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3.1.10. Evidence of either post-menopausal status or negative urinary or serum pregnancy 
test for female pre-menopausal patients.  
Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific 
requirements apply:  
− Women <50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatments and if they have luteinizing hormone and follicle-
stimulating hormone levels in the post-menopausal range for the institution 
or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, hysterectomy, or tubal ligation). 
− Women ≥50 years of age would be considered post-menopausal if they have 
been amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 
year ago, had chemotherapy-induced menopause with last menses >1 year 
ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, hysterectomy, or tubal ligation). 
If the urine test is positive or cannot be confirmed as negative, a negative serum 
pregnancy test will be required for the patient to be eligible. If patient has a positive 
serum pregnancy test, then an ultrasound must be done to rule out pregnancy in order 
to enroll on trial. 
 
3.1.11. Men and women of child bearing potential must be willing to use an adequate method 
of contraception starting with Visit 1 through 120 days after the last dose of study 
therapy. Note: Complete abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. 
 
3.1.12. Capable of giving signed informed consent including compliance with the 
requirements and restrictions listed in the informed consent form.  
3.1.13. Patient is willing and able to comply with the protocol for the duration of the study 
including treatment, scheduled visits and examinations, and follow up. 
3.2. Exclusion Criteria  
 
3.2.1. Candidate for surgical resection.  
 
3.2.2. Concurrent enrolment in another clinical study, unless it is an observational (non-
interventional) clinical study or during the follow-up of an interventional study. 
 
3.2.3. Patients who have had major surgery 28 days prior to first dose of the study drug 
excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and 
biliary stent placement. 
 
3.2.4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumour embolization, 


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14
monoclonal antibodies) ≤ 14days prior to the first dose of study drug. If sufficient 
wash-out time has not occurred due to the schedule or PK properties of an agent, a 
longer wash-out period will be required, as agreed by AstraZeneca, MedImmune, 
Syndax, and the investigator. 
3.2.5. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy 
with the exception of alopecia, vitiligo, neuropathy and the laboratory values defined 
in the inclusion criteria  
− Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Study Physician. 
− Patients with irreversible toxicity not reasonably expected to be exacerbated 
by treatment with durvalumab or SNDX-6352 may be included only after 
consultation with the Study Physician.  
3.2.6. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non–cancer-related conditions 
(e.g., hormone replacement therapy) is acceptable. 
3.2.7. History of allogenic organ transplantation. 
 
3.2.8. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
checkpoint inhibitor-induced immune mediated reaction or Wegener syndrome 
[granulomatosis 
with 
polyangiitis, 
Graves' 
disease, 
rheumatoid 
arthritis, 
hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: 
− Patients with vitiligo or alopecia. 
− Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable 
on hormone replacement. 
− Any chronic skin condition that does not require systemic therapy. 
− Patients without active disease in the last 5 years may be included but only 
after consultation with the study physician. 
− Patients with celiac disease controlled by diet alone. 
3.2.9. Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social 
situations that would limit compliance with study requirement, substantially increase 
risk of incurring AEs or compromise the ability of the patient to give written informed 
consent. 
3.2.10. History of another primary malignancy except for: 
− Malignancy treated with curative intent and with no known active disease ≥5 
years before the first dose of IP and of low potential risk for recurrence 


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− Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
− Adequately treated carcinoma in situ without evidence of disease 
3.2.11. History of leptomeningeal carcinomatosis. 
3.2.12. Brain metastases or spinal cord compression. Patients with suspected brain 
metastases at screening should have an MRI (preferred) or CT each preferably with 
IV contrast of the brain prior to study entry.  
3.2.13. History of active primary immunodeficiency. 
3.2.14. Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with 
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), 
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients 
with a past or resolved HBV infection (defined as the presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA. 
3.2.15. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or SNDX-6352. The following are exceptions to this criterion: 
− Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra 
articular injection) 
− Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or its equivalent 
− Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
3.2.16. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 
days after the last dose of IP. 
3.2.17. Female patients who are pregnant or breastfeeding or expecting to conceive or father 
children within the projected duration of the study, starting with the screening visit 
through 120 days after the last dose of study drug. 
3.2.18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug 
excipients. 
3.2.19. Prior randomization or treatment in a previous durvalumab and/or SNDX-6352 
clinical study regardless of treatment arm assignment.  
3.2.20. Patients with prolonged heart rate-controlled QTc measurements (using Fredericia’s 
formula), defined as ≥ 450 msec or other factors that increase the risk of QT 
prolongation or arrhythmic events (family history of long QT interval syndrome). 
Bundle branch block and prolonged QTcF interval may be permitted with approval 


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of the medical monitor.  
 
3.3. Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 
 
4. TREATMENT PLAN 
 
4.1. Agent Administration 
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in Section 5.2.  
Subjects will initially receive one 28-day cycle of single agent treatment with durvalumab on cycle 
1 day 1 (week 2).  In subsequent cycles, patients will receive durvalumab on day1 and SNDX-
6352 on days 1 and day 15 of each 28-day cycle. Patients will continue 28-day cycles of the 
combination therapy until disease progression.   
 
Patients will undergo intra-arterial therapy (IAT) with biopsy prior to start of cycle 1 
immunotherapy (week 1) and after completion of cycle 2 (week 9). An additional biopsy will be 
performed prior to cycle 2 (week 6) treatment. An interventional radiologist in the study team will 
determine whether the patient is a candidate for chemo- vs. radio-embolization based on imaging 
criteria specified below. The determination on which type of IAT the patient should receive is not 
a randomization process, but is made according to the criteria below.  Every subject will receive 
at least two IAT treatments, each approximately 8 weeks apart.  Whether the patients should 
receive additional IAT treatments will be at the discretion of interventional radiologists. All IAT 
treatments an individual patient receives will be the same type (Y90 or cTACE). 
 
Criteria for selecting method of Intra-Arterial Therapy (IAT) 
 
 
Y90 (radio-embolization): MRI imaging with any of the following criteria: 
• Multifocal disease with ≥ 6 lesions 
• Bilobar location 
• Size ≥ 6 cm 
 


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cTACE (Chemo-embolization): MRI imaging with any of the following criteria: 
• Unifocal or multifocal disease < 6 lesions. 
• Size < 6 cm 
 
Table 1: Study Regimen (listed in order of administration) 
 
Agent 
Premedications 
Dose 
Route1 
Schedule 
Durvalumab 
No prophylactic pre-medications 
unless indicated by previous 
experience in an individual subject 
1500 mg 
IV over 60 
minutes 
Day 1 of each 28-day 
cycle (Q4W) 
SNDX-6352 
No prophylactic pre-medications 
unless indicated by previous 
experience in an individual subject 
3mg/kg 
IV over 30 
minutes 
Day 1 and 15 of each 
28-day cycle (Q2W) 
starting at cycle 22 
 
Not given at cycle 1 
1 Infusion times are approximate (-5min/+10 min) and may need to be adjusted based on 
subject tolerability. 
2 If treatment with SNDX-6352 and durvalumab produces recurrent (second occurrence), asymptomatic 
Grade 3 elevation in CK, without evidence of end organ damage, consider dosing SNDX-6352 every 4 
weeks after consultation with sponsor. 
If retreatment with SNDX-6352 and durvalumab subsequently produces Grade 3 elevation in CK 
(third occurrence), permanently discontinue SNDX-6352 and consider starting durvalumab 
monotherapy after consultation with sponsor. 
 
4.1.1. Durvalumab (IMFINZI)  
 
Durvalumab will be administered as outlined in Table 1 above. 
 
Subjects should be observed for a minimum of 30 minutes after administration of 
durvalumab, prior to the administration of SNDX-6352. 
 
4.1.2. CSF1R inhibitor SNDX-6352    
 
The dose amount required to prepare the SNDX-6352 infusion solution will be based on the 
patient’s weight in kilograms (kg). All patients should be weighed within 3 days prior to 
dosing.  If the patient experiences either a weight loss or gain >10% compared to the weight 
used for the last dose calculation, the amount of study drug must be recalculated. For weight 
change < 10%, the decision to recalculate the SNDX-6352 dose can be in accordance with 
institutional practice.   
 
A mandatory 2-hour observation period after each SNDX-6352 infusion (for potential 
infusion-related reactions) is only required following the first 4 SNDX-6352 infusions. If no 
infusion reaction occurs in relation to the first 4 infusions, the post-infusion observation 
period may be discontinued at investigator’s discretion. Patients who experience an infusion-
related reaction at any point, must continue to undergo the mandatory observation after each 
infusion. 


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SNDX-6352 must be administered in a setting with immediate access to emergency medical 
equipment and medications to manage potentially life-threatening infusion reactions (e.g., 
anaphylaxis). Medications such as steroids (e.g., dexamethasone 10 mg), epinephrine 
(1:1,000 dilution), allergy medications (e.g., IV antihistamines), bronchodilators, or 
equivalents, and oxygen should be immediately accessible.  
 
4.2. General Concomitant Medication and Supportive Care Guidelines 
 
4.2.1. Durvalumab 
 
 
 Durvalumab is a humanized monoclonal antibody. Subjects should be closely monitored for 
potential adverse reactions during antibody infusion and potential adverse events throughout 
the study.  
 
 Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 
hours if clinically indicated and monitored as necessary to determine if event meets toxicity 
criteria. 
 
4.2.1.1. Infusion Reactions 
 
Durvalumab infusion are rare occurrences.  Reactions may consist of fever, chills/rigor, 
nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness or hypertension.  Severe reactions may include acute 
respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and 
cardiogenic shock.  Patients should be closely monitored for such reactions.  Guidelines 
for patients who experience an infusion related or allergic reaction during or after 
infusion with durvalumab are shown below in Table 2. 
 
 
 


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Table 2: Guidance on Infusion and Hypersensitivity Reactions for durvalumab 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve 
and the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
durvalumab with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of 
antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but 
is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further 
trial treatment administration. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 


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4.2.2. SNDX-6352 
 
 It is recommended that patients receiving SNDX-6352 should be monitored for serum levels 
of CK; markers of liver function (e.g., levels of transaminases, LDH, bilirubin, coagulation 
disorders); muscle function; bone function; and signs indicative of inflammation (e.g., 
leukocyte alterations, C-reactive protein) and facial/periorbital swelling. 
 
 Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 
hours if clinically indicated and monitored as necessary to determine if event meets toxicity 
criteria. 
 
4.2.2.1. Infusion Reactions 
 
 As with other monoclonal antibodies, infusion-related reactions to SNDX-6352 may 
occur. Monitor patients during and following the infusion for signs and symptoms of 
infusion-related reactions from the start of the infusion until at least 1 hour after the 
end of the infusion, in an area containing resuscitation equipment and medications 
necessary for advanced life support and cardiopulmonary resuscitation. For Grade 1 or 
2 infusion-related reactions, adjust SNDX-6352 dose per Table 3. Immediately and 
permanently discontinue SNDX-6352 for Grade 3 or 4 infusion- related reactions. 
 
Table 3: Guidance on Infusion and Hypersensitivity Reactions for SNDX-6352 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
The infusion rate should be 
decreased by 50% for the duration of 
the infusion.  
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Additional pre-medication 
may be administered at the 
investigator’s discretion. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for ≤ 24 hrs 
The infusion must be stopped until 
resolution to Grade ≤1; the infusion 
may then be resumed at 50% of the 
prior infusion rate. 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Subject may be pre-medicated 
1.5h (± 30 minutes) prior to 
infusion of SNDX-6352 with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Additional pre-medication 
may be administered at the 
investigator’s discretion. 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grades 3 or 4 
Grade 3: Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
 
 
4.2.3. Immune-Related Adverse Events (irAEs) for durvalumab and SNDX-6352  
 
Immune-related AEs (irAEs) are defined as AEs of an immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology. Complete Algorithms for managing all irAEs are 
found in Appendix E.  
 
The toxicity management written in the protocol supersede the toxicity management for 
individual agents.  
   
 Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to durvalumab and SNDX-6352, 
respectively. 
 
 Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below).  It may be necessary to 
perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as 
part of evaluation of the event. 
 
4.2.4. Prohibited and Restricted Therapies 
 
Patients may not use any of the following agents during the study: 
• Any non-study anticancer or immunotherapy agent (investigational or non-
investigational) 


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• Any other investigational agents 
• Any other immunotherapy treatment, including, but not limited to: IL-2, interferon, 
anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, or anti-
CTLA-4 antibodies 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. Steroid treatment should 
be completed at least 14 days prior to resuming study-related treatments. (See Section 
5.2 for dosing delays for steroids). Further, if patients require high dose steroids, 
while on study, durvalumab can be re-administered if the steroids are tapered over a 
12-week period. The use of physiologic doses of corticosteroids may be approved 
after consultation with the IND Sponsor. Premedication with steroids for CT contrast 
allergy will be allowed if patient is unable to undergo MRI. 
• Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
 
Patients should not donate blood while participating in this study and for at least 90 days 
following the last infusion of durvalumab or SNDX-6352.  
 
4.3. Definition of an Overdose for this Protocol 
 
Overdose will be defined as a patient receiving (accidentally or intentionally): 
• ≥5 times the indicated dose of durvalumab or 
• 15% more than the recommended dose of SNDX-6352   
 
No specific information is available on the treatment of overdose of durvalumab and SNDX-6352. 
In the event of overdose, durvalumab or SNDX-6352 should be discontinued and the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated. 
 
If an adverse experience is associated with (results from) the overdose of test drug or vaccine, the 
adverse experience is reported as a serious adverse experience, even if no other criteria for serious 
are met. 
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
All reports of overdose with and without an adverse experience must be reported within 24 hours 
to the IND Sponsor, JHMI IRB (contact information can be found in Section 6.6.1). 
4.4. Contraception, Use in Pregnancy, Use in Nursing 
 
4.4.1. Contraception 
 
 The investigational agents may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if the investigational agents have transient adverse effects on the composition of 
sperm.   


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 Given the potential risk related to pharmacologically-mediated inhibition of the PD-1 
pathway, no reproductive or developmental toxicity studies were conducted with 
durvalumab. SNDX-6352 has also not been studied in pregnant women and must not be 
given to patients who are pregnant. Furthermore, animal reproduction studies have not been 
conducted with SNDX-6352. Therefore, potential effects of SNDX-6352 use during 
pregnancy are not known and the potential for developmental toxicity cannot be excluded.  
 
 For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
 
 Female subjects will be considered of non-reproductive potential if they are either:  
 
 (1) Postmenopausal (defined as at least 12 months with no menses without  
an 
alternative medical cause; in women < 45 years of age a high follicle  stimulating 
hormone (FSH) level in the postmenopausal range may be used  
to confirm a 
post-menopausal state in women not using hormonal  
contraception or hormonal 
replacement therapy. In the absence of 12  
months of  
amenorrhea, a single 
FSH measurement is insufficient.);  
 
 
OR  
 (2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral  salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to  
screening;  
 
 
OR  
 (3) Has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by agreeing to use (or have their partner use) acceptable contraception 
during heterosexual activity.  Complete abstinence is acceptable if this is the usual lifestyle 
and preferred contraception for the subject 
 
Acceptable methods of contraception are‡: 
 
Single method (one of the following is acceptable): 
− Intrauterine device (IUD) 
− Vasectomy of a female subject’s male partner  
− Contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
− 
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
− 
Cervical cap with spermicide (nulliparous women only)   
− 
Contraceptive sponge (nulliparous women only)  
− 
Male condom or female condom (cannot be used together) 
− 
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 


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progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
 
4.4.2. Use in Pregnancy 
 
 The investigational agents may have adverse effects on a fetus; therefore, women with a 
positive pregnancy test at screening will not be eligible for enrollment.  If a patient 
inadvertently becomes pregnant while on treatment with combination immunotherapy, the 
patient will immediately be removed from the study.  The pregnancy and outcome of the 
pregnancy of a patient or patient’s partner will be reported per Section 6.6.1. 
 
4.4.3. Use in Nursing Women 
 
 It is unknown whether the investigational agents are excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, patients who are breast-feeding are not eligible for enrollment. 
 
4.5. Unacceptable Toxicities 
 
 
Unacceptable toxicities are defined as any AE that is temporally related to study drug 
administration and is not due to the subject’s underlying malignancy and for which there is no 
clear evidence for an alternative etiology and meets one of the following NCI CTCAE criteria: 
 
Hematologic Toxicities  
− Grade 4 anemia  
− Grade 3 or 4 neutropenia lasting ≥ 14 days  
− Grade ≥ 3 neutropenia with fever  
− Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with clinically significant 
bleeding  
 
Non-Hematologic Toxicities  
− Treatment-related ≥ grade 4 AEs 
− Grade 3 Pneumonitis 
− Grade 3 Nephritis 


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− Grade 3 elevated LFTs that do not improve to < grade 2 after holding study drugs 
for two weeks. 
− Grade ≥ 2 eye pain or reduction of visual acuity that does not respond to topical 
therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting 
therapy, or requires systemic therapy 
− Any other Grade ≥ 3 toxicity that do not improve to ≤ grade 2 under therapy within 
2 weeks except for the following:  
o Grade 3 nausea, vomiting, or diarrhea that resolves to Grade ≤ 1 within 7 
days, with or without appropriate supportive therapy  
o Grade ≥ 3 rash that resolves to Grade ≤ 2 within 7 days  
o Grade 3 fatigue that resolves to ≤ Grade 2 within 14 days  
o Grade ≥ 3 laboratory abnormalities that, in the judgment of the 
investigator, are not clinically significant  
o Asymptomatic amylase/lipase elevation 
 
The unacceptable toxicity definition excludes the following conditions: 
− Grade 3 fatigue lasting ≤ 7 days 
− Isolated asymptomatic Grade 3 AST that is accompanied by Grade ≤1 ALT and 
total bilirubin (TB), and no changes from baseline of ALT or TB. 
− Asymptomatic Grade 3 CK for which diagnostic evaluation (per guidelines in 
Appendix E) shows no evidence of end organ damage and it reduces to Grade 2 
within 14 days of holding SNDX-6352. 
− Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the subject is asymptomatic 
− Grade 3 inflammatory reaction attributed to a local antitumor response (e.g. 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
− Concurrent vitiligo or alopecia of any AE grade 
− Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management  
− Grade 3 or 4 lymphopenia 
− Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs 
or symptoms and are reversed with appropriate maximal medical intervention 
within 3 days 
− Grade 3 fever lasting ≤ 24 hours with or without medical therapy and is not 
considered an SAE 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours if 
clinically indicated and monitored as necessary to determine if event meets toxicity criteria. 
 
In the absence of a clinically significant abnormality, repeat laboratory testing will be conducted 
to confirm significant laboratory findings prior to designation as an unacceptable toxicity. Toxicity 
that is clearly and directly related to the primary disease or to another etiology is excluded from 
this definition. 
 
The proportion of unacceptable toxicities will be monitored throughout the study. See Section 12.3 
for study stopping requirements due to toxicity.  
 


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Unacceptable toxicities require patient discontinuation from study treatment (see Section 4.6 for 
complete list of criteria requiring treatment discontinuation).   
 
4.6. Criteria for Removal from Study Treatment  
 
Patients will be removed from study treatment when any of the criteria listed below applies.  The 
reason for study treatment removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws consent  
• Patient is lost to follow-up. 
 
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent 
for treatment 
• 
Development of local recurrence or distant metastatic disease.  Patients may continue to 
receive treatment after local recurrence until progression is confirmed on subsequent scans. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) (see Section 4.5) 
• 
Investigator’s decision to withdraw the subject 
• 
Life-threatening durvalumab or SNDX-6352-related AE(s) per Appendix E 
• 
Inability to reduce corticosteroid dose for immune-related adverse reactions to ≤10 mg 
prednisone or equivalent per day up to 30 days duration 
• 
Patient’s weight falls to ≤ 30 kg 
• 
If in the opinion of the Investigator, a change or temporal or permanent discontinuation of 
therapy would be in the best interest of the patient.  The IND Sponsor should be included 
in this decision 
• 
Noncompliance with trial treatment or procedure requirements 
• 
Patient becomes pregnant 
 
4.7. Off Study/Safety Follow-up Visit 
 
After a patient is discontinued from treatment, a mandatory Off Study/Safety Follow-Up Visit 
should be performed approximately 30 days after the last infusion of study medication (or within 
7 days prior to initiation of a new anti-cancer treatment, whichever comes first).  Procedures and 
assessments performed at this visit and beyond should follow the respective guidelines described 
in Section 9.  The patient will be monitored for adverse events up to the mandatory Off 
Study/Safety Follow-Up Visit or to resolution of toxicity to Grade 0-1, whichever occurs later.  
Serious Adverse Events (SAEs) that occur within 90 days of the last infusion of durvalumab or 
before initiation of a new antineoplastic treatment should also be followed and recorded. 
 


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4.8. Duration of Follow Up   
 
Subjects who discontinue from treatment should continue to follow up with their primary 
oncologist and be contacted every six months (with a +/- 1 month window) to monitor OS and for 
potential disease progression.  Radiology reports may be collected for patients who came off study 
for reasons other than cancer progression. Information of other cancer therapies after 
discontinuation from the study treatment will be collected. 
  
Subjects who are discontinued from the study treatment due to an unacceptable drug-related AE 
will be monitored for safety until the resolution of the AE to ≤ grade 1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. 
  
All subjects will be followed for at least 30 days after their last dose of study drug for the 
development of AEs. SAEs that occur within 90 days of the last infusion of durvalumab or before 
initiation of a new antineoplastic treatment should also be followed and recorded. 
 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1. Dose Modifications 
 
Dose reduction or dose increase of durvalumab or SNDX-6352 will not be permitted. 
 
5.2. Dosing Delays 
 
When the dosing of durvalumab is delayed, the dosing SNDX-6352 must also be delayed, and vice 
versa. Dosing may be held for up to 1 week.  In this case, subsequent cycles should continue given 
that the dosing is a minimum of 2 weeks apart and they have not experienced an AE(s) 
necessitating discontinuation.  If delayed more than 1 week, the Principal Investigator must be 
contacted for further instructions on continued treatment.   
Durvalumab and SNDX-6352 will be withheld for suspected drug-related toxicities and severe or 
life-threatening AEs as per Appendix E. Additional guidance for toxicity management can be 
found in Appendix E.   
 
Dosing of study therapy will be delayed if the following laboratory criteria are not met:  
Absolute neutrophil count     > 1,000 cells/mm3 
Hemoglobin                           > 8 g/dL 
Platelets                                 > 50,000 cells/mm3 
Serum creatinine                    ≤ 1.5 x ULN 
CPK1 
≤ 5 x ULN (or ≤ 2.5 x ULN with clinical or lab signs of end 
organ damage / increased urine or serum myoglobin) 
AST and ALT2                         ≤ 3.0 x ULN 
Total bilirubin                       ≤ 1.5 x ULN  
 
In case toxicity does not resolve or improve to ≤ Grade 1 within 12 weeks after last administration 
of study drug, study therapy discontinuation should be considered after discussion with the 


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Principal Investigator and IND Sponsor.  With IND Sponsor and Drug Sponsor agreement, patients 
still at Grade 2 may continue in the study only if asymptomatic and controlled.   
 
Two dosing delays due to the same toxicity will be permitted.  In the event of a third occurrence 
of the same toxicity which would require dosing delay, study therapy will be discontinued 
permanently. 
 
1. SPECIAL NOTE FOR ELEVATED CK: If retreatment with SNDX-6352 and 
durvalumab produces recurrent (second occurrence) asymptomatic Grade 3 elevation in CK, 
without evidence of end organ damage, consider dosing SNDX-6352 every 4 weeks after 
consultation with sponsor. If retreatment with SNDX-6352 and durvalumab produces 
recurrent (third occurrence) Grade 3 elevation in CK, permanently discontinue SNDX-6352 
and consider starting durvalumab monotherapy after consultation with sponsor. 
 
2. SPECIAL NOTE FOR ELEVATED AST: Patients who develop isolated Grade 2 
AST elevation (i.e. without concurrent ALT or bilirubinemia to suggest a liver source of 
transaminase) may continue dosing with combined immunotherapy of durvalumab and 
SNDX-6352 since this elevation is thought to be due to pharmacodynamics effect rather 
than direct muscle toxicity. However, if there is grade 2 AST elevation with concurrent 
ALT or bilirubin elevation, then adjust treatment was written in Appendix E for grade 2 
AST, ALT, bilirubin abnormality. 
 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 for adverse 
event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected, recorded, and followed as appropriate.  
 
The PI has the primary responsibility for continuous internal monitoring for safety, protocol 
compliance, and identification, grading, coding, and required reporting of all anticipated and 
unanticipated adverse events and protocol problems. Although this responsibility is usually shared 
among the PI, research nurse, and data manager, the PI is ultimately responsible for grading and 
attribution of all events. 
 
6.1. Definitions 
 
6.1.1. Adverse Event (AE) 
 
 Adverse event is defined as any undesirable sign, symptom or medical condition occurring 
after starting the study drug (or therapy) even if the event is not considered to be related to 
the study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 


J2031 Protocol - Version 3.0 / February 7, 2022 
29
findings, electrocardiogram). Medical conditions/diseases present before starting the study 
treatment are only considered adverse events if they worsen after starting the study treatment 
(any procedures specified in the protocol). Adverse events occurring before starting the study 
treatment but after signing the informed consent form will not be recorded. Abnormal 
laboratory values or test results constitute adverse events only if they induce clinical signs or 
symptoms or require therapy. 
 
 Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as adverse events. A grade 1 or 2 clinical laboratory abnormality should be 
reported as an adverse event only if it is considered clinically significant by the investigator, 
requires the participant to have a study drug discontinued or interrupted, or requires the 
participant to receive corrective therapy. 
 
6.1.2. Serious Adverse Event (SAE) 
 
 A serious adverse event (SAE) is an undesirable sign, symptom or medical condition which:  
• Results in death  
• Is life threatening (defined as an event in which the subject 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 for exceptions) > 24 hours 
• 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 [e.g., 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 home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose 
 
 Events not considered to be serious adverse events are hospitalizations for the:  
• A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
• Elective surgery, planned prior to signing consent 
• Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy)  
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases  


J2031 Protocol - Version 3.0 / February 7, 2022 
30
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
6.1.3. Events of Clinical Interest (ECI)  
 
Events of clinical interest for this trial include: 
• An overdose of study drug, as defined in Section 4.3, that is not associated with 
clinical symptoms or abnormal laboratory results.  
• Hy’s Law: AST or ALT ≥3X ULN and total bilirubin ≥2X ULN and, at the same 
time, an alkaline phosphatase < 2X the ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic 
tests that may require an additional evaluation for an underlying etiology.  
An adverse event of special interest (AESI) is one of scientific and medical interest 
specific to understanding of the Investigational Product and may require close 
monitoring. An AESI may be serious or non-serious.  
 
If the Investigator has any questions in regards to an event being an ECI, the Investigator 
should promptly contact the Study Physician. 
 
6.1.4. Adverse Events of Special Interest (AESI)  
 
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and rapid 
communication by the Investigator. An AESI may be serious or non-serious. The rapid 
reporting of AESIs allows ongoing surveillance of these events in order to characterize and 
understand them in association with the use of this investigational product. 
 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI 
that is associated with drug exposure and is consistent with an immune-mediated mechanism 
of action and where there is no clear alternate etiology. Serologic, immunologic, and 
histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes of the imAE. 
 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician. 
 
AESIs observed with durvalumab include: 
o Diarrhea / Colitis and intestinal perforation 
o Pneumonitis / ILD 
o hepatitis / transaminase increases 


J2031 Protocol - Version 3.0 / February 7, 2022 
31
o Endocrinopathies 
(i.e. 
events 
of 
hypophysitis/hypopituitarism, 
adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
o Rash / Dermatitis 
o Nephritis / Blood creatinine increases 
o Pancreatitis / serum lipase and amylase increases   
o Myocarditis 
o Myositis / Polymyositis 
o Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
o Other inflammatory responses that are rare / less frequent with a potential 
immune-mediated aetiology include, but are not limited to, pericarditis, 
sarcoidosis, uveitis and other events involving the eye, skin, haematological and 
rheumatological events. 
o Infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab Investigator’s Brochures. More specific guidelines for their 
evaluation and treatment are described in detail in the Dosing Modification and Toxicity 
Management Guidelines (please see Appendix E). These guidelines have been prepared by 
the Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating 
these types of toxicities.  These guidelines apply to AEs considered causally related to the 
study drug/study regimen by the reporting investigator 
 
Reporting forms are found in Appendices B and C.  
 
6.2. Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
• No (unrelated, not related, no relation):  The time course between the administration of study 
drug and the occurrence or worsening of the adverse event rules out a causal relationship and 
another cause (concomitant drugs, therapies, complications, etc.) is suspected.  
• Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
• The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.  
• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have.  
• Concomitant medication - The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be recognized 
to cause the event in question.  


J2031 Protocol - Version 3.0 / February 7, 2022 
32
• Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.  
• Exposure to physical and/or mental stresses - The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.  
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should be 
considered. 
 
6.3. Grading 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 5.0) and graded as shown below: 
 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experience by the subject. 
 
6.4. Expectedness 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or frequency from 
information on the investigational drug/agent provided in the Investigator’s Brochure, package 
insert or safety reports. Any adverse event that is not included in the informed consent is 
considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the Investigator’s 
Brochure. An adverse event is considered “expected”, only if it is included in the informed consent 
document as a risk. 
 
6.5. Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor will notify investigators of all SAEs that 
are unexpected (i.e. not previously described in the Investigator Brochure), and definitely, 
probably, or possibly related to durvalumab or SNDX-6352. This notification will be in the form 
of an expedited safety report (ESR) that is to be faxed to the investigators and the study 
coordinators. Upon receiving such notices, the investigator must review and retain the notice with 
the Investigator’s Brochure and where required by local regulations, the investigator will submit 
the ESR to the appropriate IRB. The investigator and IRB will determine if the informed consent 




J2031 Protocol - Version 3.0 / February 7, 2022 
34
A copy of the MedWatch report must be emailed to AstraZeneca and Syndax at the time the 
event is reported to the FDA. It is the responsibility of the sponsor to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca and 
Syndax at the same time. 
 
A cover page should accompany the MedWatch form indicating the following: 
• “Notification from an Investigator Sponsored Study” 
• The investigator IND number assigned by the FDA 
• The investigator’s name and address 
• The trial name/title and AstraZeneca/Syndax ISS reference number (ESR-16-11978) 
 
Sponsor must also indicate, either in the SAE report or the cover page, the causality of events 
in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
 
6.6.1.1 Deaths  
All deaths that occur during the study, or within the protocol-defined 90-day post-last 
dose of durvalumab safety follow-up period must be reported to AstraZeneca and 
Syndax as follows: 
• Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
• Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to AstraZeneca and Syndax 
as a SAE within 24 hours as described above. The report should contain a 
comment regarding the co-involvement of progression of disease, if 
appropriate, and should assign main and contributory causes of death.  
• Deaths with an unknown cause should always be reported as a SAE.  
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab 
safety follow-up period will be documented as events for survival analysis, but will not 
be reported as an SAE. However, if an investigator learns of any SAEs, including death, 
at any time after the patient has been permanently withdrawn from study, and he/she 
considers there is a reasonable possibility that the event is related to study treatment, the 
investigator should notify the study sponsor, AstraZeneca/MedImmune, and Syndax 
Drug Safety. 
6.6.1.2 Overdose 
An overdose is defined in Section 4.3 of this protocol. Any overdose of a study drug is 
required to be reported within 24 hours of knowledge of the event to the IND sponsor, 
AstraZeneca/ MedImmune, and Syndax Patient Safety.  
 
If an overdose of study drug is taken without any associated clinical symptoms or 
abnormal laboratory results, the overdose will be reported as a non-serious Event of 


J2031 Protocol - Version 3.0 / February 7, 2022 
35
Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
 
If an AE is associated with (results from) an overdose of study drug, the overdose will 
be reported as a serious adverse experience, even if no other criteria for serious are met. 
Any AE resulting from an overdose must also be recorded in the AE log. Overdose 
does not automatically make the associated AE serious, but if the consequences of the 
overdose are serious, for example death or hospitalization, the event is serious and must 
be recorded and reported as an SAE.  
 
There is currently no specific treatment in the event of an overdose of durvalumab or 
SDNX-6352. The investigator will use clinical judgment to treat any overdose. 
 
6.6.1.3 
Hepatic function abnormality 
Hepatic function abnormality that fulfills the criteria of a potential Hy’s Law case (see 
criteria in Section 6.1.3) , with or without associated clinical manifestations, is required 
to be reported as an ECI (“hepatic function abnormal”) within 24 hours of knowledge 
of the event to the sponsor and AstraZeneca and Syndax Patient Safety authorities using 
the contact information described above, unless a definitive underlying diagnosis for 
the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed.  
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study patient 
will be based on the clinical judgment of the investigator. 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study patient must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the 
investigator and evaluated by the sponsor and AstraZeneca/MedImmune and Syndax.  
6.6.1.4 
Pregnancy 
If a patient becomes pregnant during the course of the study, the IPs should be 
discontinued immediately.  
 
Pregnancy itself or pregnancy of the patient’s partner is not regarded as an AE unless 
there is a suspicion that the IP under study may have interfered with the effectiveness 
of a contraceptive medication. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be 
followed up and documented even if the patient was discontinued from the study. 
Congenital abnormalities or birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. 
 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca and Syndax representatives 


J2031 Protocol - Version 3.0 / February 7, 2022 
36
within 24 hours of when he or she becomes aware of it. The designated AstraZeneca 
and Syndax representatives will work with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca and Syndax Patient Safety data entry site 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies. The 
same timelines apply when outcome information is available.  
 
Where a report of pregnancy in a patient’s partner is received, prior to obtaining 
information about the pregnancy, the Investigator must obtain the consent of the 
patient’s partner. Therefore, the local study team should adopt the generic ICF template 
in line with local procedures and submit it to the relevant Ethics Committees 
(ECs)/Institutional Review Boards (IRBs) prior to use.  
 
6.6.2. Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
All serious adverse events will be reported to the IRB per institutional guidelines. Follow-up 
information will be submitted to the IRB as soon as relevant information is available. 
 
6.6.3. Food and Drug Administration (FDA) 
 All reporting to the FDA will be completed by the IND Sponsor. 
 
6.6.3.1. Expedited IND Safety Reports: 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the 
investigational agent.  Such reports are to be telephoned or faxed (
) to 
the FDA within 7 calendar days of first learning of the event.   
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND Safety 
Report.   
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with 
the IND concerning similar events should be analyzed.  The new report should contain 
comments on the significance of the new event in light of the previous, similar reports. 
Follow-up information will be submitted to the FDA as soon as relevant information is 
available. 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA within 15 calendar days of first learning of the event.  
 
6.6.3.2. 
IND Annual Reports 
 In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report of the 
adverse events and progress of the investigation.  Please refer to Code of Federal 
Regulations, 21 CFR § 312.33 for a list of the elements required for the annual report.  
All IND annual reports will be submitted to the FDA by the IND Sponsor. 








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40
 
 
 
 
 
 
 
 
 
   
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.8. Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to subjects, and the amount remaining at the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
 


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41
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1. Tumor and Immune Biology Correlative Studies 
 
We will conduct correlative studies in further understanding the role of anti-PD-1 and anti-CSF1R 
antibody treatments in modulating tumor biology and immune biology, which will include, but not 
limited to the following objectives. One important goal of the clinical trial is to assess the effects 
of anti-PD-L1 antibody in combination with SNDX-6352 on the PD-L1/PD-1 and PD-L1/PD-1 
associated pathways, M1 vs. M2 tumor-associated macrophages (CD68/iNOS vs. CD68/CD163), 
Th1 vs. Th2 vs. Th17, and Teff vs. Treg, and granzyme B+ CD8 T cells.  
 
8.1.1. Multiplex Immunohistochemistry 
 
Multiplex IHC of immune parameters including PD-L1 and PD-1 and a comprehensive 
analysis of tumor microenvironment will be performed on FFPE slides of pre-treatment and 
post- treatment core biopsy specimens using a previously established protocol30. We will 
examine the densities and distribution of effector T cell (Teff) markers including CD8 and 
Granzyme B, expression of immune suppressive signals including PD-1, PD-L1, and IDO1,  
immune activation signals including CD137(4-1BB) on T cells, and macrophage markers as 
described below, and the expression of T helper cell differentiation markers including Tbet 
(for Th1), GATA3 (for Th2), RORγT (for Th17), and Foxp3 (for Treg). Quantification of 
IHC on immune markers will be conducted as described previously30 and will be supervised by 
our pathologist (Dr. Elizabeth Thompson).   
 
8.1.2. Monocyte/Myeloid cell Response to CSF-1R inhibition 
 
The response to CSF-1R inhibition can be measured using serum CSF-1 levels using ELISA 
and observing whether changes in their levels correlate with clinical response to CSF-1R 
inhibition. In addition, levels of CD14 (dim) CD16 (+) monocyte subsets in peripheral 
mononuclear cells can be measured using flow cytometry and also correlated with clinical 
response. Intratumoral response to CSF-1R inhibition will be measured by IHC of 
monocytes/macrophages (M1 vs. M2, DC, etc.) as described previously30 on the FFPE slides 
of pre- and post-treatment biopsy specimens. 
 
8.1.3. T cell Response to CSF-1R inhibition 
 
Explorative Peripheral and Tumor-infiltrating T cell Repertoire Analysis: As part of 
explorative studies, we will also use next-generation sequencing to examine the T cell 
receptor (TCR) repertoire expressed by TIL prior to versus post durvalumab/CSF1Ri 
treatment and to compare with peripheral blood lymphocytes (PBL). We will determine if T 
cells in PBL undergo clonal expansion following the treatment, whether treatment-expanded 
T cell clones traffic to the TME. 
 
Through our Next-Generation Sequencing CORE, whole exome sequencing (WES) will be 
performed on paired patient tumor and normal DNA isolated from FFPE tumor tissue and 
cryopreserved PBL respectively to identify tumor-specific non-synonymous mutations. RNA 
sequencing will be performed in parallel to confirm expression of mutant genes identified by 
WES. Expressed nonsynonymous mutations will be screened for candidate neoepitopes 


J2031 Protocol - Version 3.0 / February 7, 2022 
42
using NetMHC HLA-binding predictions and a NetMHC cutoff binding score of 500. 
Predictions will be made for each tumor-matched HLA class I and class II molecule. We will 
determine whether the total number of expressed mutations, and/or the total number of 
predicted neoepitopes for each patient’s tumor correlates with improved overall or disease-
free survival. 
 
Tumor antigen-specific T cells that traffic into the tumor are the most relevant T cells to 
study when evaluating antitumor immune responses. We will use a more comprehensive 
approach and examine the TCR repertoire in PBL and TIL using a next-generation 
sequencing approach established by Adaptive Biotechnologies. Using Adaptive’s approach, 
we will specifically sequence the complementarity-determining region 3 (CDR3) of the TCR 
beta chain variable segment (TCR Vbeta). Sequencing will be performed on genomic DNA 
isolated from cryopreserved PBL and FFPE tumor tissue specimens. We will compare TCR 
repertoires in pre vs. post durvalumab/CSF1Ri treatment PBL and in pre- vs. post-treatment 
biopsy specimens from the same patients to identify TCR’s expressed by T cells that expand 
following treatment. We will also compare TCR repertoires in PBL vs TIL from the same 
patients to identify any T cell clones that are induced or expanded in PBL by CSF-1R/PD-
L1 blockade and also enriched in TIL. We will use these data to determine if T cells in PBL 
and TIL undergo clonal expansion following CSF-1R/PD-L1 blockade treatment, and if so, 
whether the treatment-expanded T cell clones traffic to the TME. 
 
 
8.1.4. Plasma collection for ctDNA analysis 
 
Plasma will be collected and stored for circulating tumor DNA (ctDNA) measurement and 
comparison.  
 
8.2. Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnoses 
immune related toxicities.  
 


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43
9. STUDY SCHEDULE 
Procedure 
Screen 
 
IAT 
1 
Cycle 1 
D1     D15 
Cycle 2 
D1     D15    D22   
Cycle 3 
D1    D15 
Cycle 4 
D1    D15 
Repeat through 
end of treatment 
EOT 
Visit14 
Safety 
Follow-
Up 
Survival 
Follow-
Up15 
Cycle 5 
D1    D15 
Wk 
1 
Wk 
2 
Wk 
4 
Wk 
6 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
12 
Wk 
14 
Wk 
16 
Wk  
18 
Wk  
20 
30 days 
from last 
dose  
90 days 
from last 
dose 
Q6 months 
Visit Window1 
-28 to 0 
- 
+7 
+3 
+7 
+3 
+7 
+7 
+3 
+7 
+3 
+7 
+3 
+14 
+14 
(±1 month) 
IAT2 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Durvalumab 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
SNDX-6352 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Demographics, Med Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam3 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Vital signs, height4 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Performance Status3 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Hematology profile5,6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry profile 6,7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
EKG6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR and PT6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH6,8 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Pregnancy9 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
HIV, HBC, HCV10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Adverse events3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Con meds3 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
CT or MRI11 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Tumor measurements 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
Biopsy12, 16 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Research Blood 6, 13, 16  
- PBMC (up to 100cc)  
- plasma (up to 20cc) 
- serum (up to 5cc)  
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Survival/ progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


J2031 Protocol - Version 3.0 / February 7, 2022 
44
 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-person clinical trial visits or portions of clinical trial visits where 
determined to be appropriate and where determined by the investigator not to increase the participants risks. Prior to initiating telemedicine for study visits the study team will explain 
to the participant, what a telemedicine visit entails and confirm that the study participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will 
be obtained in accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed feasible, the study visit will proceed as an in-person visit. 
Telemedicine visits will be conducted using HIPAA compliant method approved by the Health System and within licensing restrictions. 
1. Longer delays to be approved by the IND Sponsor. Delays are listed in days unless otherwise specified. 
2. All subjects will receive at least two IAT treatments (cTACE or Y90). Patients may receive additional IAT treatments at the discretion of interventional 
radiologists. All IAT treatments will be the same type. 
3. Focused physical examinations will be conducted.  Physical exams, performance status, con med, and AE assessments can be made up to 3 days prior to 
infusion. 
4. Height and pulse oximetry will be obtained at screen only. Blood pressure, pulse, and temperature will be measured at each indicated visit and at the following 
times on infusion days:  
• 
Durvalumab: Prior to infusion (any time prior), 30 minutes into infusion (± 5min), at the end of infusion (± 5min) 
• 
SNDX-6352: Start of infusion (0 min ± 5min), at the end of infusion (± 5min), and at 1 and 2 hours post-infusion (± 5min).  The 2-hour post-SNDX-
6352 vitals may be discontinued after the first 4 infusions provided no infusion reactions have occurred 
5. CBC with differential including absolute eosinophil count, absolute neutrophils, absolute lymphocytes, and platelets. 
6. Labs and research bloods may be collected within a window of up to 4 days prior to dosing. Unexpected Grade 3 or greater laboratory abnormalities should 
be repeated within 24-72 hours if clinically indicated and monitored as necessary to determine if event meets toxicity criteria. 
7. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium, CK, LDH, CRP, amylase, lipase. 
8. FT3 and FT4 to be checked reflexively if TSH is abnormal. 
9. For WOCBP only. Serum or urine pregnancy tests must be repeated with each subsequent therapy (collected within a window of up to 3 days prior to dosing). 
10. HIV-1/2 Ab, HBV surface antigen (HBsAg), anti-HBV core antibody (anti-HBc), and anti-HCV antibody 
11. Radiologic evaluations (CT chest, abdomen, and pelvis with contrast) and tumor measurements will be performed. MRI will be done for those with contrast 
allergies. Interval scans may be done up to 7 days prior to the infusion/visit. Following the second scan (prior to second IAT), scans will be repeated 
approximately every 8 weeks (-1/+2 weeks) or every other cycle 
12. Research biopsies will be performed during IAT procedure on Week 1, up to 1 week prior to Cycle 2 treatment, and during the IAT procedure on Week 9.  Up 
to 6 core biopsies will be collected at each time point. 
13. Research blood collected at baseline (screen), Week 9, and Week 18 only (not repeated at subsequent cycles).  Detailed instructions for blood collection, 
processing, and storage are provided in the Laboratory Manual. 
14. EOT Clinical assessments do not need to be repeated if they were done within last 7 days.  EOT Scans do not need to be repeated if done within the past 6 
weeks. 
15. Subjects who discontinue treatment will be followed (by phone, email, or visit) every 6 months (± 1 month) after completion of EOT visit to monitor overall 
survival.  Information on other cancer therapies and disease status will also be collected. In addition, SAEs that occur within 90 days (+14 day reporting 
window) of the end of treatment or before initiation of a new antineoplastic treatment should also be followed and recorded. 
16. Research samples will be collected at the discretion of the PI based on availability of supplies and safety of patient and staff.


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10. MEASUREMENT OF EFFECT 
 
10.1. Definitions 
 
 Evaluable for toxicity. Subjects are evaluable for toxicity if they receive at least one dose of 
durvalumab or SNDX-6352. 
 
 Evaluable for objective response.  All patients who have received at least one dose of 
immunotherapy and have at least one post-baseline tumor assessment or discontinue due to toxicity 
or clinical progression prior to post-baseline tumor assessments will be considered evaluable for 
response.  Response criteria will be classified by modified RECIST (mRECIST) criteria 
(Appendix D) 
 
10.2. Methods for Evaluation of Measurable Disease 
 
 All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.  Subjects will be evaluated for anti-
tumor effect by follow-up imaging (CT Chest/Abd/Pelvis, PET-CT imaging, MRI 
Chest/Abd/pelvis) as outlined above. All subsequent scans (post-treatment) will be compared to 
the same pretreatment CT, PET/CT, or MRI that was used prior to initiating of study 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. 
 
 Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for 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 
immune-related 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. 
 
 
 
 


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46
11. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event guidelines and instructions for AE reporting can be found in Section 6 (Adverse 
Events: List and Reporting Requirements). 
 
11.1. Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study staff. These 
data will be reviewed for completeness and accuracy by the Principal Investigator.  
 
11.2. Safety Meetings 
 
Scheduled meetings will occur on a regular basis with the frequency dependent on the rate of 
subject accrual and the progress of the study. Meetings will include the protocol principal 
investigator, study coordinator(s), research nurses(s), sub-investigators (as appropriate), 
collaborators (as appropriate), and biostatisticians (as appropriate) involved with the conduct of 
the protocol. During these meetings matters related to the following will be discussed: safety of 
protocol participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), data completeness, and progress of data for objectives. 
 
11.3. Monitoring 
 
This study is under the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC). 
Data monitoring of this protocol will occur on a regular basis with the frequency dependent on the 
rate of subject accrual and the progress of the study.  The protocol will be monitored internally by 
the Principal Investigator. The SKCCC Compliance Monitoring Program will provide external 
monitoring for JHU-affiliated sites in accordance with SKCCC DSMP (Version 6.0, 
02/21/2019).  The SMC Subcommittee will determine the level of patient safety risk and 
level/frequency of monitoring. 
   
Dr. Lei Zheng will be holding the IND for this study.  He will comply with all regulated reporting 
requirements to the FDA. 
 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1. Sample Size 
 
This single arm phase 2 study aims to evaluate safety and efficacy of the combination of IAT 
durvalumab, and CSF-1R inhibitor (SNDX-6352) in 30 patients with unresectable intrahepatic 
cholangiocarcinoma.  The primary endpoint is objective response (CR or PR) per mRECIST 
criteria. We plan to enroll up to 30 patients which results in 26 patients evaluable for objective 
response. The trial is design to demonstrate an improvement of ORR to 50% (alternative 
hypothesis) from a historical baseline of 25% or lower (null hypothesis).  
 
Our group previously reported a retrospective analysis of 198 ICC patients who received IAT, 
including conventional transarterial chemoembolization (cTACE) (64.7%), drug-eluting beads 


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47
(DEB) (5.6%), bland embolization (TAE) (6.6%), or yttrium-90 radio embolization (23.2%)5.  In 
this historical control cohort, assessment of tumor response revealed complete or partial response 
in 25.5% patients, while 61.5% had stable disease; 13.0% had progressive disease. Median 
overall survival was 13.2 months and did not differ on the basis of the type of IAT. Another 
study showed similar results while demonstrated that objective response rate following the initial 
session of IAT is 11%. In general, the patients would be observed without any therapy following 
IAT. Systemic therapy may be given following IAT, but would not result in any objective 
response. Objective response rate of approximately 20% is seen in other malignancies treated 
with single agent anti_PD-1. Therefore, we wish to test if the ORR of IAT followed by 
durvalumab and SNDX-6352 is higher than 25%. The minimum required level of efficacy that 
would warrant further study with the proposed regimen is a 50% ORR.  The sample size is 
calculated to detect an improved ORR from 25% to 50%. A Simon’s two stage minimax design 
is planned. A total of 11 patients will be entered in the first stage. If <=2 subjects show objective 
response (CR or PR), the treatment will be terminated and we will conclude the regimen is 
ineffective. If >=3 subjects respond, then additional 15 patients will be enrolled.  If a total of 9 or 
fewer subjects respond in stage one and two combined, we consider the regimen ineffective. If a 
total of 10 or more respond, we conclude the regimen is promising and warrant further study. 
The maximum sample size will be 26 evaluable patients. The design has 90% power to detect an 
absolute 25% increase of ORR with one-sided type I error 0.09 (target type I error rate 0.1). The 
chance of early stopping is 0.46 when the ORR is 25%.  
 
12.2. Primary Analysis 
 
Objective response is defined as complete response (CR) or partial response (PR) per mRECIST. 
The ORR will be estimated as the proportion of patients who have CR or PR during the treatment, 
along with the 95% exact confidence intervals. Patients who receive at least one dose of 
durvalumab or SNDX-6352 and have at least one post-baseline tumor assessment or discontinue 
due to toxicity or clinical progression prior to post-baseline tumor assessments are evaluable for 
ORR.  
 
For safety evaluation, we will use count, and proportion with a 95% exact confidence interval to 
summarize toxicity per patient (total number of treated patients as the denominator), and per 
treatment cycles (total number of cycles as the denominator). Safety analysis population are 
patients who receive at least one dose of durvalumab or SNDX-6352. 
 
Secondary endpoints include PFS, OS and duration of response. PFS is defined as the time from 
the date of first IAT until the date of disease progression (by mRECIST criteria) or death (by any 
cause in the absence of progression), whichever occurs earlier. For patients who have not 
progressed, relapsed, or died at the time of analysis, PFS will be censored on the date of last 
recorded tumor assessment.  OS is defined as the time from the date of first IAT until death, and 
censored at the date of last known alive for those who do not die. The Kaplan-Meier survival curve 
of PFS and OS will be constructed and the corresponding 95% pointwise confidence intervals (CI) 
will be derived based on standard deviation of the log transformed survival function. e. The median 
PFS and OS together with its 95% CI will also be reported. Among the patients who have CR or 
PR, duration of response (DOR) is the time interval from initial response to the documented tumor 
progression. Median DOR will be estimated using Kaplan-Meier method, and swimmers plot will 
be used to demonstrate DOR.  
 


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12.3. Safety monitoring plan 
 
Toxicity will be monitored continuously through the course of treatment.  Occurrence of grade 3 
or higher immune-related hepatotoxicity attributable to study drugs at any time will be 
considered as a primary endpoint for purposes of this stopping rule. If the risk of these adverse 
events appears to be higher than 15%, we will temporarily halt the study pending safety 
investigation and dose modification. Specifically, we apply a Bayesian toxicity monitoring rule 
that suspends the enrollment if the posterior probability of risk being larger than 15% is 0.7 or 
higher. The monitoring rule uses beta (0.5, 2.5) as prior distribution. This means that our prior 
guess at the proportion of severe immune-related hepatotoxicity is 17%, and 90% probability that 
the rate of this AE is below 45%. Starting from the 3rd patient, the decision rule for toxicity 
stopping is as follows: 
 
Stop if number of patients experiencing 
grade 3 or higher hepatotoxicity ≥:  
2 
3 
4 
5 
6 
In number of patients between: 
3 - 8 
9 - 13 
14 - 19 20 - 25 
26 
 
Operating characteristics based on 10,000 simulations: 
 
Additionally, if unacceptable toxicities (as defined in Section 4.5) occur in >30% of subjects, 
then enrollment will be suspended until further review and consideration by the IND Sponsor 
and IRB. 
 
12.4. Analysis of Immune Measurements 
 
The list of immune markers is shown in Section 8. Continuous variables will be summarized with 
means or medians and standard deviations. Dichotomous and categorical variables will be 
summarized using proportions with exact 95% confidence intervals and counts, respectively. 
Summaries for both pre and each time of post administration of immunotherapy will be computed. 
Plots (e.g. scatterplots, boxplots, and spider plots) will be used to show the changes in immune 
markers over time. The change of markers after treatment will be compared using paired t-tests (or 
Wilcoxon signed-rank tests if appropriate) for continuous variables and McNemar's tests for 
dichotomous variables. The associations between immune parameters and clinical outcomes (OS 
and PFS) will be evaluated using univariate and multivariate Cox regression models. 
 
 
Risk of severe hepatotoxicity 
.05 
.10 
.15 
.20 
.25 
0.3 
% of Time Study Stops 
6.6% 
26.1% 
51.6% 
72.1% 
87.1% 
95.1% 
Expected Sample Size 
24.8 
21.5 
17.3 
13.6 
10.4 
8.2 


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49
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Zhu, Y. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and 
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29 
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APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX B: Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Please notify within 24 hours: 
IND Sponsor
 
AstraZeneca (
 
Syndax: 
 
 
Protocol Title: A Phase II Study of durvalumab in combination with a CSF-1R Inhibitor Following 
Chemo or Radio-Embolization for Patients with Intrahepatic Cholangiocarcinoma 
Protocol #:  
 
Principal Investigator: 
 
Signature of PI: 
 
Date: 
 
Report Type:       
  
Initial          
Follow-up          
Final Follow-up          
Addendum to: 
Section A: Subject Information 
Subject ID: 
 
Age (years): 
Gender: 
Male  
Female 
Section B: Event and Study Drug Information 
Type of Intra-
arterial Therapy 
(IAT) Received: 
Y90    
cTACE 
 
 
Durvalumab 
SNDX-6352 
Total Dose: 
1500 mg 
 
Date of First Dose: 
 
 
Date of Last Dose  
Prior to Event: 
 
 
# of Total Doses: 
 
 
Action Taken  
w/ study drug 
 None     
 Interrupted 
Discontinued   
Delayed 
 None   
 Interrupted 
Discontinued   
Delayed 
Dates of IAT: 
Event Abated after 
use stopped/ reduced? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Event Reappeared 
After Reintroduction? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Event diagnosis or symptoms: 
 
Event Grade: 
Event Onset Date: 
 
Event End Date: 
 
Date Event Discovered: 
 
Relationship to: 
Durvalumab 
SNDX-6352 
Y90/cTACE 
Underlying Disease 
Unrelated 
 
 
 
 
Related 
 
 
 
 


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Section C: Brief Description of the Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section D: Relevant Tests/Laboratory Data 
 
Section E: Relevant Medical History 
 
 
Section F: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section G: Comments 
Additional Documents Attached (labs, scans, notes, etc.): 
 Please specify, including dates 
 
 
 


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54
APPENDIX C: SAE Reporting Form 
 
Serious Adverse Event Reporting Form 
 
Please notify within 24 hours: 
IND Sponsor 
) 
AstraZeneca (
 
Syndax: 
 
 
Protocol Title: 
 
A Phase II Study of durvalumab in combination with a CSF-1R Inhibitor Following 
Chemo or Radio-Embolization for Patients with Intrahepatic Cholangiocarcinoma 
Protocol #:  
 
Principal Investigator: 
 
Signature of PI: 
 
Date: 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria / Outcome 
(check all that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Persistent or Significant Disability 
 Congenital / Birth Defect 
 Other Important Medical Event 
 New Cancer 
 AE associated with Overdose 
Hospital 
Admission Date:  
 
 
SAE ID: 
 
 
Hospital 
Discharge Date: 
 
Date Event 
Discovered: 
 
 
Section A: Subject Information 
Subject ID: 
 
Age (years): 
Gender: 
Male  
Female 
Section B: Event and Study Drug Information 
Event diagnosis or 
symptoms: 
Event Grade: 
Cause of Death  
(if applicable): 
Event Outcome: 
 Recovering 
 Recovered 
 Recovered with sequelae 
 Not Recovered 
 Death 
 Unknown 
Event Onset Date: 
 
Event End Date: 
 
Date of Death (if applicable): 
 
Section C: Study Drug Information 
Investigational Product: Durvalumab (1500 mg IV), SNDX-6352 (3mg/kg IV) 
Indication: intrahepatic cholangiocarcinoma 
Type of Intra-
arterial Therapy 
(IAT) Received: 
Y90    
cTACE 
 
Durvalumab 
SNDX-6352 
Total Dose (mg):  
1500 mg 
 
Date of First Dose: 
 
 
Date of Last Dose  
Prior to Event: 
 
 
# of Total Doses: 
 
 


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Dates of IAT: 
Action Taken  
w/ study drug 
None   
Interrupted 
Discontinued   
Delayed 
None   
Interrupted 
Discontinued   
Delayed 
Event Abated after use 
stopped/ reduced? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Event Reappeared 
After Reintroduction? 
Yes    
No    
N/A 
Yes    
No    
N/A 
Relationship to: 
Durvalumab 
SNDX-6352 
Y90/cTACE 
Underlying Disease 
Unrelated 
 
 
 
 
Related 
 
 
 
 
Section C: Brief Description of the Event 
 
 
 
 
 
 
 
 
 
 
Section D: Relevant Tests/Laboratory Data 
 
Section E: Relevant Medical History 
 
 
Section F: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section G: Comments 
Additional Documents Attached (labs, scans, notes, etc.): 
 Please specify, including dates 
 
 
 


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APPENDIX D:  Modified Response Evaluation Criteria in Solid Tumors 
(mRECIST) Criteria 
 
Definitions  
Target Lesions should meet ALL the following criteria: 
• The lesion can be classified as a RECIST measurable lesion (i.e. can be accurately 
measured in at least 1 dimension as 1 cm or more) 
• The lesion is suitable for repeat measurement 
• The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI 
 
Non-Target Lesions are those that meet ANY of the following criteria: 
• Fails to meet one of more target lesion criteria above 
• An infiltrative-type mass with ill-defined borders that therefore does not appear suitable 
for accurate and repeat measurements 
• A lesion previously treated with locoregional or systemic treatments if the lesion is poorly 
demarcated or exhibits atypical enhancement as a result of the previous intervention 
 
Assessment of target lesion response 
• Complete response (CR): Disappearance of any intratumoral arterial enhancement in all 
target lesions. 
• Partial response (PR): At least a 30% decrease in the sum of diameters of viable 
(enhancement in the arterial phase) target lesions, taking as reference the baseline sum of 
the diameters of target lesions.  
• Stable disease (SD): Failure to meet the criteria for either partial response or progressive 
disease. 
• Progressive disease (PD): An increase in at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since treatment started.  
 
Assessment of non-target lesion response 
• Complete response (CR): Disappearance of any intratumoral arterial enhancement in all 
non-target lesions. 
• Incomplete response/Stable Disease (IR/SD): Persistence of intratumoral arterial 
enhancement in one or more non-target lesions.  
• Progressive disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  
 
 
 


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Specific recommendations in mRECIST 
• Measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and non-
enhancing necrotic tissue is the highest 
• The longest diameter of the viable tumor is not necessarily located in the same plane in 
which the baseline diameter was measured: a thorough careful evaluation of the scans is 
required 
• The measurement of the viable tumor diameter should not include any major intervening 
areas of necrosis 
• Pleural effusion or ascites: Cytopathologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required to declare PD. 
• Porta hepatis lymph node: Lymph nodes detected at the porta hepatis can be considered 
malignant if the lymph node short axis is at least 2 cm.  
• Portal vein thrombosis: Malignant portal vein thrombosis should be considered as a non-
measurable lesion and thus included in the non-target group.  
• New lesion: A newly detected intrahepatic lesion can be classified as intrahepatic 
cholangiocarcinoma—and therefore will be declared as evidence of progression—when 
its longest diameter is at least 1 cm and the nodule shows the typical vascular pattern of 
intrahepatic cholangiocarcinoma on dynamic imaging, that is, peripheral rim-like 
enhancement or hyperenhancement in the arterial phase with progressive or stable 
enhancement in the portal venous or late venous phase.  
• Liver lesions larger than 1 cm that do not show a typical vascular pattern can be 
diagnosed as intrahepatic cholangiocarcinoma by evidence of at least 1 cm interval 
growth in subsequent scans.   
• An individual radiologic event will be adjudicated in retrospect as progression at the time 
it was first detected by imaging techniques, even if strict criteria were fulfilled only at 
subsequent radiologic testing 
 
Overall Response Assessment by mRECIST 
Target Lesions 
Non-Target Lesions New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 


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