Clinical trial NCT02732015
Conditions: Locally Advanced Sarcoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2016-10-12; Completion date: 2020-07-10
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well rolapitant hydrochloride works in preventing nausea/vomiting in patients with sarcoma receiving chemotherapy. Antiemetic drugs, such as rolapitant hydrochloride, may help control or prevent nausea and vomiting in patients treated with chemotherapy.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the effect of rolapitant hydrochloride (rolapitant) on nausea/vomiting in patients with sarcoma receiving multi-day highly emetogenic chemotherapy (HEC) regimen of doxorubicin and ifosfamide (AI).

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of rolapitant in patients receiving AI regimen. II. To evaluate the effects of rolapitant on patient reported outcomes.

OUTLINE:

PART I: Patients receive dexamethasone intravenously (IV) daily and ondansetron IV on days 1-5, and rolapitant hydrochloride orally (PO) on day 1.

PART II: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive treatment as in part I. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive dexamethasone IV and ondansetron IV on days 1-5, and fosaprepitant dimeglumine IV over 30 minutes on days 1 of cycle 2. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

CHEMOTHERAPY: All patients receive doxorubicin IV over 72 hours, mesna IV, and ifosfamide IV over 3 hours on days 1-4 or 1-5. Patients with sarcomas of small cell histology receive vincristine sulfate IV on day 1. Cycles repeat every 3 weeks following blood count and patient recovery from any acute toxicities.

Arms: arm 1: Patients receive treatment as in part I. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

CHEMOTHERAPY: All patients receive doxorubicin IV over 72 hours, mesna IV, and ifosfamide IV over 3 hours on days 1-4 or 1-5. Patients with sarcomas of small cell histology receive vincristine sulfate IV on day 1. Cycles repeat every 3 weeks following blood count and patient recovery from any acute toxicities. arm 2: Patients receive dexamethasone IV and ondansetron IV on days 1-5, and fosaprepitant dimeglumine IV over 30 minutes on days 1 of cycle 2. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.

CHEMOTHERAPY: All patients receive doxorubicin IV over 72 hours, mesna IV, and ifosfamide IV over 3 hours on days 1-4 or 1-5. Patients with sarcomas of small cell histology receive vincristine sulfate IV on day 1. Cycles repeat every 3 weeks following blood count and patient recovery from any acute toxicities.
Interventions: intervention 1: Dexamethasone intervention 2: Doxorubicin intervention 3: Fosaprepitant Dimeglumine intervention 4: Ifosfamide intervention 5: Laboratory Biomarker Analysis intervention 6: Mesna intervention 7: Ondansetron intervention 8: Questionnaire Administration intervention 9: Rolapitant Hydrochloride intervention 10: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV intervention 7: Given IV intervention 8: Ancillary studies intervention 9: Given PO intervention 10: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 23 
October 28, 2019  
 
Effects of Rolapitant on Nausea/vomiting in Patients with Sarcoma Receiving 
Multi-day Highly Emetogenic Chemotherapy (HEC) with Doxorubicin and 
Ifosfamide Regimen (AI) 
 
1.0 Objectives  
 
Primary Objective: 
To evaluate the effect of Rolapitant on nausea/vomiting in patients with sarcoma 
receiving multi-day HEC regimen of Doxorubicin and Ifosfamide (AI). 
 
Secondary Objectives: 
(1) To evaluate the toxicity of Rolapitant in patients receiving AI regimen. 
(2) To evaluate the effects of Rolapitant on patient reported outcomes. 
  
2.0  Background 
 
2.1 Chemotherapy-induced Nausea and Vomiting (CINV) 
Nausea and vomiting are one of the most debilitating side effects of cytotoxic 
chemotherapy. CINV is a frequent adverse event that can impair the quality of life in 
cancer patients (1, 2). The time course of CINV is well recognized for single-day 
chemotherapy regimens. It may persist for several days and has frequently been 
classified as having an acute phase (starting within 24 hours of the chemotherapy 
administration) and a delayed phase (starting approximately 16-24 hours after initiation 
of chemotherapy and lasting to approximately 120 hours post-chemotherapy).  There 
are both acute (0 to 24 hours) and delayed phases of CINV which are distinct after HEC 
but less differentiated after MEC. Active management of CINV reduces patient suffering 
and increases the likelihood that cancer patients will continue to receive potentially life-
saving treatment at appropriate doses.  
 
2.2 Prevention/Treatment for CINV 
CINV is triggered by multiple factors involving patients’ characteristics and type of 
chemotherapy regimen. Several neurotransmitters, located in the gastrointestinal (GI) 
tract or in the central nervous system (CNS), are involved with the pathophysiology of 
CINV, triggering the emetic center located in the medulla (3). These include histamine, 
acetylcholine, serotonin, dopamine, and substance P (4-7). The acute phase, the first 
24 hrs following chemotherapy treatment, is mediated largely by chemotherapy-induced 
increases in serotonin (5-HT3) release and activation of 5-HT3 receptors on vagal 
afferent neurons in the gut. 5-HT3 receptor antagonists (5-HT3RA) are clinically 
effective in preventing acute CINV, particularly when given in combination with 
corticosteroids such as dexamethasone (8).  
 
Delayed CINV occurs from 2 to 5 days after chemotherapy and has a different etiology 
than acute CINV (9). Antiemetic therapy with a corticosteroid and 5-HT3RA, particularly 
with the first generation 5-HT3RA, is less effective during the delayed as compared to 


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the acute phase of CINV. The primary etiology of delayed CINV appears to involve the 
release of the neurokinin peptide substance P in the brainstem. When an NK1  
antagonist, 5-HT3RA, and corticosteroid are given in combination, there is a greater 
reduction in CINV compared to that seen with the use of the combination of a 5-HT3RA 
antagonist and corticosteroid alone. The NK1 receptor antagonist aprepitant was 
approved by the FDA and by the EMA for the prevention of acute and delayed CINV 
associated with HEC, including high-dose cisplatin, and MEC when used in combination 
with a 5-HT3RA and corticosteroids (10). Although aprepitant and fosaprepitant (iv 
formulation) are effective, dosage adjustment of other concomitantly administered drugs 
is necessary because aprepitant is a mixed inducer/inhibitor of cytochrome P450 (CYP) 
3A4 and also affects other CYP enzymes. Furthermore, aprepitant requires several 
doses during each cycle of chemotherapy (11-14). 
 
2.3 CINV in Sarcoma Patients Receiving AI regimen 
AI is multi-day regimen of highly emetogenic chemotherapy, with high incidence of 
delayed CINV. Fosaprepitant, NK1 receptor antagonist (RA), administered IV as single 
dose is FDA-approved, in combination with 5HT3RA and dexamethasone has improved 
the control of emesis. However, delayed N/V still remains problematic (9).  We, 
therefore investigated the effects of fosaprepitant administered IV on day 1 vs days 1 
and 4 on CINV and the effect on ifosfamide (Ifex) and its active metabolites, due to 
potential drug interactions via CYP450. Patients planned to receive AI, were 
randomized 1:1 to Arm A (single- dose fosaprepitant on day 1) or Arm B (2-doses, on 
days 1 and 4). Blood samples were drawn for levels of Ifex/metabolites to be analyzed 
at the end of study. All patients could receive 2 doses during cycles 3-6. Pts were 
monitored for N/V with daily symptom diary and FLIE (functional living index -- emesis) 
score (days 1, 5 and 10). 40 eligible pts were randomized. Fosaprepitant administered 
as 2 doses resulted in significantly better control of delayed N/V as compared to single-
dose or the control cycle (response rate 10% and 17% vs 50%, respectively) (15, 16). 
Fosaprepitant had minor effects on Ifex and metabolites levels, which was partly 
compensated by autoinduction.  
 
2.4 Rolapitant, A New NK-1 Receptor Antagonist 
Rolapitant (formerly referred to as SCH 619734) is a potent, selective, competitive 
neurokinin-1 (NK1) receptor antagonist with no known activity at other pharmacologic 
targets (17). It binds with high affinity to the human NK1 receptor (Ki = 0.66 nM) and 
competitively antagonizes functional effects mediated by activation of the NK1 receptor 
in cultured cells (Kb = 0.45 nM). The endogenous activator of NK1 receptors is the 
neuropeptide Substance P (18). Rolapitant does not have significant affinity for NK2 or 
NK3 receptors or for a battery of other receptors, transporters, enzymes, and ion 
channels. The compound is active in animal models of CINV and has demonstrated 
efficacy in Phase 2 studies in patients receiving HEC. Rolapitant has been free of 
clinically relevant drug interactions in studies conducted to date, has rapid and good 
brain penetration which may contribute to its quick onset of action, and a long half-life 
that allows for dosing only once during each cycle of chemotherapy. PET occupancy 
studies as well as clinical efficacy data support the use of only a single dose of 
rolapitant to protect patients for 5 days from CINV (19, 20).  


Page 3 of 23 
October 28, 2019  
 
 
2.4.1 Preclinical Studies 
Rolapitant has been evaluated in a series of non-clinical toxicity studies of up to 6 
months duration in rats and up to 9 months duration in monkeys by oral administration 
and up to 14 days duration in rats and up to 1 month duration in monkeys by 
intravenous (IV) infusion. Developmental and reproductive toxicity studies, genetic 
toxicity studies, and safety pharmacology studies were also conducted. In addition, 
genetic toxicity studies and a safety pharmacology study were conducted with the 
pharmacologically active metabolite SCH 720881 (M19). Furthermore, 2-year oral 
carcinogenicity studies of rolapitant in rats and mice have been completed. 
 
The major findings in the non-clinical toxicity studies reported to date are convulsions in 
rats, mice, and monkeys at high lethal or near lethal doses (oral administration) and in 
monkeys (after IV infusion) as well as developmental and reproductive findings in 
female rats. For convulsions, exposure margins have been identified in the non-clinical 
species relative to clinical exposure data at an oral dose of 180 mg and there has been 
no evidence of treatment-related seizures in the completed clinical trials. Since the 
rolapitant clinical development program has not nor will include women who are 
pregnant or attempting to become pregnant, the findings in the developmental and 
reproductive studies in rats are not considered relevant for the clinical trials in CINV. 
The mouse carcinogenicity study with rolapitant was negative; the rat carcinogenicity 
study showed a non-significant increase in thyroid follicular cell tumors and benign 
adrenal medullary tumors. 
 
To evaluate the IV administration of rolapitant in humans, blood compatibility and local 
tolerance studies were also performed. The results from the in vitro blood compatibility 
study as well as animal studies indicate that the intended clinical formulation does not 
cause hemolysis in human, rat or monkey blood. The local tolerance study showed that 
the intended formulation is well tolerated when administered by either the intended IV 
route or potential misdose routes. Additionally, results obtained from the 14-day IV rat, 
14-day IV monkey and one-month IV monkey studies indicate rolapitant is well tolerated 
at 20 mg/kg/day in rats and up to 15 mg/kg/day in monkeys. These results also 
indicated that the solubilizing agents in the rolapitant IV formulation are well tolerated at 
10 mL/kg when administered at the defined concentration, approximately 5-fold higher 
than the maximal infusion volume (1.58 mL/kg, 95 mL/60 kg human) anticipated 
clinically.  
 
2.4.2 In vivo Activity of Rolapitant 
Ferrets have proven to be a useful animal model of chemotherapy-induced emesis, and 
have been used extensively to demonstrate the antiemetic effects of drugs, including 
NK1 receptor antagonists like aprepitant. Rolapitant produced a dose-dependent 
inhibition of retching and vomiting with an ED50 of 0.07 mg/kg when dosed orally to 
ferrets 4 hrs prior to cisplatin treatment.  Moreover, a single 1 mg/kg oral dose of 
rolapitant given 4 hrs prior to cisplatin substantially inhibited both the acute and delayed 
retching and vomiting for 72 hrs. Cisplatin-induced retching and vomiting was also 


Page 4 of 23 
October 28, 2019  
 
completely abolished (ca. >95%) by once daily oral administration of 1 mg/kg of 
rolapitant for 3 days after cisplatin treatment. 
 
In conclusion, the IV and oral monkey studies have shown that the safety profile of 
rolapitant is similar at the NOAEL/maximum tolerated dose following administration of 
rolapitant by either the IV or oral route of administration. Moreover, the systemic toxicity 
profiles and exposure levels are comparable between IV and oral administrations at 
these dose levels. 
 
2.4.3 Clinical Experience 
The total number of subjects exposed to oral rolapitant is approximately 2,800, 
which includes 1,567 CINV patients and 1,231 healthy volunteers or patients 
from several additional Phase 1 and Phase 2 studies (21). Rolapitant was well 
tolerated at single doses up to 800 mg or as a once-daily dose up to 50 mg for 10 
days. Orally administered rolapitant was completely bioavailable, rapidly 
absorbed, and slowly cleared. Maximum concentrations of a 200 mg dose were 
approximately 1000 ng/mL and were achieved by approximately 4 hrs. The half-
life was approximately 170 hrs (average), suggesting that a single dose may be 
sufficient to prevent CINV during both the acute and delayed phases of CINV. 
Rolapitant is highly bound to plasma proteins, with an unbound (free) fraction of 
<1%. Urinary excretion of the dose is minor, and the major route of elimination is 
via the feces. Rolapitant is extensively metabolized by oxidation, primarily to 
M19, an equipotent human NK1 receptor antagonist. The formation and 
elimination of M19 are slow. 
 
In Phase 1 drug interaction studies, administration of rolapitant did not alter the 
pharmacokinetics of midazolam, dexamethasone or ondansetron, drugs 
metabolized by cytochrome P450 3A4. This indicates lack of a clinically relevant 
inhibition of CYP3A4 by rolapitant. Moreover, the PK of repeated doses of 
dexamethasone was also unaffected by a single 200 mg (equivalent to the 180 
mg free base dose in the treatment section) oral dose of rolapitant, indicating a 
lack of significant CYP3A4 induction by rolapitant or its metabolite. Inhibition of 
CYP3A4 by concomitant agents is unlikely to affect the PK of single doses of 
rolapitant, since concentrations of both rolapitant and the active metabolite M19 
were unaffected by repeated daily oral doses (400 mg) of the potent CYP3A4 
inhibitor ketoconazole. 
 
In a recently conducted drug interaction study to assess the effect of rolapitant on 
the pharmacokinetics of specific probe substrates, preliminary results indicate 
that rolapitant increased the PK exposure of dextromethorphan, a CYP2D6 
substrate, digoxin, a P-gp substrate,  and sulfasalazine, a BCRP substrate 
suggesting that rolapitant is a moderate inhibitor of CYP2D6 and an inhibitor of 
P-gp and BCRP. Therefore, dosage adjustments may be warranted for sensitive 
CY2D6 substrates and/or P-gp, BCRP transporter substrates when given 
concomitantly with rolapitant. However, Rolapitant did not alter the 


Page 5 of 23 
October 28, 2019  
 
pharmacokinetics of tolbutamide, omeprazole, efavirenz or repaglinide, drugs 
metabolized by CYP2C9, CYP2C19, CYP2B6, or CYP2C8 respectively.  
In a recently conducted PK study in subjects with impaired hepatic function, 
preliminary results indicate comparable rolapitant PK profiles were observed in 
subjects with mild hepatic impairment and a slight decrease in exposure with 
subjects with moderate hepatic impairment when compared to healthy subjects. 
Therefore, dose adjustment for rolapitant when administered to patients with mild 
to moderate hepatic impairment is not required. Subjects with severe hepatic 
impairment were not evaluated in this study.  
 
A human ECG study demonstrated no effects of rolapitant 200 mg or 800 mg (4 
times the therapeutic dose) on the QTc interval. A clinical PET study 
demonstrated that single oral doses of rolapitant ranging from 5 to 200 mg can 
block the occupancy of cortical NK1 receptors by the selective PET ligand 11C-
GR205171. After a 200 mg dose, over 90% of central NK1 receptors remained 
blocked for at least 5 days. 
 
The results from the dose range-finding study showed rolapitant administered as 
a single dose of 200 mg with a 5-HT3 receptor antagonist and dexamethasone to 
be highly effective in the prevention of CINV following HEC, together with data 
from the Phase 1 PET study, led to the dose selection and design of three global 
multicenter, randomized, parallel-group, double-blind, active-controlled Phase 3 
studies conducted in subjects receiving HEC (P04832 and Study P04833) and in 
subjects receiving MEC (Study P04834).  
 
These studies were designed to evaluate the efficacy of a single dose of 
rolapitant 200 mg administered orally with granisetron and dexamethasone 
compared to placebo administered with granisetron and dexamethasone for the 
prevention of delayed phase CINV (>24 to 120 hours). The primary endpoint of 
all three studies was achieved (21-24). Specifically, the proportion of subjects 
who had no emesis and no use of rescue medication during the delayed phase of 
CINV, >24 through 120 hours following initiation of HEC or MEC, was 
significantly higher for subjects receiving rolapitant compared with subjects 
receiving placebo (71.4% vs. 60.9%, respectively, p < 0.001). Likewise, the 
proportion of subjects who had no emesis and no use of rescue medication was 
significantly higher for subjects receiving rolapitant compared with subjects 
receiving placebo during the acute phase (< 24 hours) (83.5% vs. 78.7%, 
respectively, p = 0.003) and during the overall phase (0-120 hours) (68.7% vs. 
58.1%, respectively, p < 0.001). Multiple secondary and tertiary endpoint 
comparisons favored the rolapitant group in the individual studies and in the 
pooled analyses and contribute additional support for the benefit of rolapitant 
during the delayed, acute and overall at risk period (0 to 120 hours) for patients 
receiving emetogenic chemotherapy. In addition, rolapitant was safe and well 
tolerated. No AEs were clearly attributable to administration of rolapitant, and 
neurological and other clinical and laboratory examinations did not detect specific 
safety signals that could be ascribed to rolapitant. 


Page 6 of 23 
October 28, 2019  
 
 
2.4.4 Drug Interaction 
 
2.4.4.1 Effect of Rolapitant on Other Drugs 
Rolapitant is not an inhibitor nor an inducer of CYP3A4. Therefore, no dosage 
adjustment for dexamethasone (CYP3A4 substrate) is needed when co-
administered (25).  
 
Rolapitant is a moderate CYP2D6 inhibitor, an inhibitor of Breast-Cancer-
Resistance Protein (BCRP) and an inhibitor of P-glycoprotein (P-gp).  
 
CYP2D6 Substrates with a Narrow Therapeutic Index: Increased plasma 
concentration of CYP2D6 substrates may result in potential adverse reactions. A 
three-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, 
was observed 7 days after a single dose of Rolapitant. The duration of CYP2D6 
inhibition was not studied beyond 7 days and may last longer. Concomitant use 
with thioridazine is contraindicated. Avoid use of Rolapitant with pimozide. 
Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a 
narrow therapeutic index cannot be avoided (25). 
 
BCRP Substrates with a Narrow Therapeutic Index (e.g., methotrexate, 
topotecan, or irinotecan): Increased plasma concentrations of BCRP substrates 
may result in potential adverse reactions. Monitor for adverse reactions related to 
the concomitant drug if use of Rolapitant cannot be avoided. Use the lowest 
effective dose of rosuvastatin. 
 
P-gp Substrates with a Narrow Therapeutic Index: Increased plasma 
concentrations of digoxin, or other P-gp substrates, may result in potential 
adverse reactions. Monitor for increased digoxin concentrations. Monitor for 
adverse reactions if concomitant use of Rolapitant with other P-gp substrates 
with a narrow therapeutic index cannot be avoided (25).  
 
2.4.4.2 Effect of Other Drugs on Rolapitant 
Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma 
concentrations of rolapitant can decrease the efficacy of Rolapitant; avoid use of 
Rolapitant in patients who require chronic administration of such drugs (25). 
 
2.4.5 Rationale for the Study 
The NK1 antagonist aprepitant was approved by the FDA and by the EMA for the 
prevention of acute and delayed CINV associated with HEC, including high-dose 
cisplatin, and moderately emetogenic chemotherapy (MEC) when used in 
combination with a 5-HT3 antagonist and corticosteroid. Although aprepitant is 
effective, dosage adjustment of concomitantly administered drugs is necessary 
because aprepitant is a mixed inducer/inhibitor of cytochrome P450 (CYP) 3A4 
and also affects other CYP enzymes. Furthermore, aprepitant requires several 
doses during each cycle of chemotherapy. Rolapitant has been free of clinically 


Page 7 of 23 
October 28, 2019  
 
relevant drug interactions in studies conducted to date, has rapid and good brain 
penetration which may contribute to its quick onset of action, and a long half-life 
that allows for dosing only once during each cycle of chemotherapy. PET 
occupancy studies as well as clinical efficacy data support the use of only a 
single dose of rolapitant to protect patients for 5 days from CINV. AI is a highly 
emetogenic regimen with the potential for improvement in delayed 
nausea/vomiting with rolapitant in addition to 5HT3RA and steroids.  
 
2.4.6 Study Update 
To date, 28 patients have been enrolled on to this study, all of them have 
completed more than 1 cycle of treatment. The treatment of Rolapitant is well 
tolerated. In the first cohort- Cohort 1 (dexamethasone 12 mg on day 1, and 8 mg 
on days 2-5), none of the 9 patients had complete response in days 1-10. Since 
there is no interaction between Rolapitant and CYP3A4, the amendment 2 was 
written to keep the dose of dexamethasone constant at 12 mg on Days 2-5 for 
Part 1 (Rolapitant). In this new cohort- Cohort 2 (dexamethasone 12 mg on days 
1-5), the complete response rate (no emetic episodes and no rescue 
medications) was 29%  (5/19) in days 1-10; and the complete response rate was 
32% (6/19) for emetic episodes only related to chemotherapy. We therefore 
would like to expand our experience with the current regimen to confirm the 
response rate prior to initiation of Part 2 of the study. 
 
3.0  Background Drug Information 
 
3.1 Rolapitant 
For this trial, Rolapitant will be supplied by TerSera as investigationally-labelled 
commercial supply. 
 
A. Physical Description of Study Drug   
Rolapitant will be provided as Rolapitant, 90 mg, (equivalent to 100 mg rolapitant 
hydrochloride monohydrate) tablets for oral administration.  Tablet appearance is blue 
modified capsule shaped tablet debossed on one side with T0101 and 100 on the other.  
 
B. Packaging, labeling, and Storage 
The drug product will be supplied in blister packs containing two (2) 90 mg, (equivalent 
to 100 mg rolapitant hydrochloride monohydrate) tablets provided by TerSera.  Study 
drug supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the drug supply label.  Rolapitant tablets are stored at Controlled 
Room temperature, 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) (25).  
  
C. Additional Clinical Supplies  
For additional supplies, the pharmacist will coordinate the dispatch of supplies to the site. 
 
D. Drug Accountability   
It is the responsibility of the clinical investigator or trained designee to ensure that all 
study drug received at the site is inventoried and accounted for throughout the study by 


Page 8 of 23 
October 28, 2019  
 
the designated personnel and is recorded in the inventory log kept with the pharmacy 
study documentation. The drug accountability will be verified by a trained designee 
upon completion of the study. Study drug will be stored in a secured area with restricted 
access to the dosing preparers only.  
The clinical investigator or trained designee must store all study drug pending 
reconciliation. The investigator agrees that study drug(s) will be dispensed by the 
investigator or sub-investigator(s) named on the Investigator Agreement or their 
qualified designees.  The investigator, sub-investigators, or qualified designees also 
agree that the study drug(s) will be dispensed only to study subjects who have provided 
written informed consent and have met all entry criteria and in accordance with the 
instructions provided in the pharmacy manual.  
After study drug reconciliation, the clinical site may destroy used/unused study drug 
product locally in accordance with all applicable institutional standard operating 
procedures, local and federal laws. Documentation of such destruction must be 
recorded and provided TerSera. If the clinical site does not have the appropriate 
procedures in place to handle final disposition of clinical supplies, the clinical site will be 
instructed to return the clinical supplies to TerSera.  
 
3.2 Fosaprepitant  
Fosaprepitant iv will be used from the commercial source. 
 
3.3 Other Drugs 
Doxorubicin, ifosfamide, vincristine, mesna, and hematopoietic growth factors are all 
commercially available drugs (see dose modification table in Section 5.3). 
 
 
4.0  Patient Eligibility 
 
Inclusion Criteria 
• Patients with sarcoma which is locally advanced, at high risk for relapse or 
metastatic for whom treatment with doxorubicin plus ifosfamide (AI) or AI and 
vincristine (VAI) is indicated.  
• Must be 18 to 65 years of age.  
• Patient must have an estimated life expectancy ≥ 4 months in the opinion of 
the investigators. 
• Male and Females of child bearing potential must use acceptable methods of 
birth control which include oral contraceptives, spermicide with either a 
condom, diaphragm or cervical cap, us of a intrauterine device (IUD) or 
abstinence. 
• Female patients must have a negative pregnancy test at Screening 
• Female patients of childbearing potential must agree to use an acceptable 
method of birth control (excluding hormonal birth control methods) for 72 


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hours prior to admission and to continue its use during the study and for at 
least 30 days after the final dose 
• Male patients must agree to use an acceptable form of birth control from 
study Day 1 through at least 30 days after the final dose 
 
 
• Adequate hematologic (ANC > 1500/mm3, platelet count > 100,000/mm3), 
renal (serum creatinine < 1.5mg/dL), hepatic [serum bilirubin count < 1.5 x 
upper limit normal (ULN) and SGOT or SGPT < 2.5 x ULN, for subjects with 
known liver metastases < 5 x ULN] functions. 
• Karnofsky Performance Status > 60%. (Appendix D) 
• Signed informed consent form. 
• Patients are required to read and understand English to comply with protocol 
requirements. 
 
Exclusion Criteria 
a. Any current treatment, medical history, or uncontrolled condition, other than 
malignancy, (e.g., alcoholism or signs of alcohol abuse, seizure disorder, medical or 
psychiatric condition) that, in the opinion of the investigator, would confound the 
results of the study or pose any unwarranted risk in administering study drug to the 
subject  
b. Patient has a known hypersensitivity to the administration of any prescribed oral or 
intravenous study medication or metabolite, including but not limited to, a history of 
hypersensitivity to the drugs or their components, severe renal impairment, severe 
bone marrow suppression, or systemic infection  
c. Patient is a woman with a positive urine or serum pregnancy test within 3 days prior 
to study drug administration, is breast-feeding, or is planning to conceive children 
within the projected duration of the study treatment 
d. Patient has taken the anti-emetic agents within the last 48 hours prior to the start of 
treatment with study drug:  
• 5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.). 
Palonosetron is not permitted within 7 days prior to administration of 
investigational product  
• Phenothiazines 
(prochlorperazine, 
fluphenazine, 
perphenazine, 
thiethylperazine, chlorpromazine, etc.)  
• Benzamides (metoclopramide, alizapride, etc.)  
• Domperidone  
• Cannabinoids  
• NK1 antagonist (aprepitant)  
• Benzodiazepines (lorazepam, alprazolam, etc) 
• herbal medications or preparations in doses designed to ameliorate nausea 
or emesis  
 
e. Patient 
has 
received 
systemic 
corticosteroids 
or 
sedative 
antihistamines 
(dimenhydrinate, diphenhydramine, etc.) within 72 hours of Day 1 of the study except 


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October 28, 2019  
 
as premedication for chemotherapy (e.g., taxanes). Subjects who are receiving 
inhaled steroids for respiratory conditions or topical steroids for skin disorders can be 
enrolled  
f. Patient has symptomatic primary or metastatic CNS disease  
g. Patient has ongoing vomiting, retching, dry heaves, or clinically significant nausea 
caused by any etiology, or has had such symptoms within 24 hours prior to the start 
of Day 1 of the study intervention, or has a history of anticipatory nausea and vomiting  
h. Patient must not have been dosed with test drug or blinded study drug in another 
investigational study within 30 days or 5 half-lives of the biologic activity of the test 
drug, whichever is longer, before the time of first study dose 
i. Patient who is participating in any investigational agent that is not FDA-approved. 
j. Patient has uncontrolled angina, congestive heart failure (New York Heart Association 
> class II or known ejection fraction < 40%), uncontrolled cardiac arrhythmia or 
hypertension, or acute myocardial infarction within 3 months. 
k. Prior surgery or radiotherapy (RT) within 2 weeks of study entry. 
l. Psychological, social, familial, or geographical reasons that would prevent scheduled 
visits and follow-up. 
 
 
5.0  Treatment Plan 
 
5.1 Study Drug Treatment 
This study will be conducted in 2 parts, part I and Part II, as follows: 
 
Part I: 
This part will be a single-arm phase II study of rolapitant administered as single-dose on 
Day 1. In this part, we will estimate the preliminary efficacy of rolapitant administered on 
day 1 by evaluating complete response (CR) in the single arm setting.  
 
Up to 42 patients will be enrolled in part 1 (after the amendment 4) using the Simon’s 
Minimax 2-stage design; 24 patients will be enrolled in the first stage. If ≥ 2 out of 24 
patients experience CR, additional 18 patients will be enrolled. The trial will be stopped 
early if less than 8 patients have complete response in nausea/vomiting. 
 
With conclusion of Part 1 of study, communication of Part 1 study results will be 
presented to TerSera. In addition, publication of Part 1 study results may be presented 
for poster abstract and/or scientific journal for publication. 
 
 
The decision to move on to Part II of this study will not depend on the results of the 
patients who have been treated with dexamethasone at 8 mg on Days 2-5. Rather, if the 
first part of the trial for the patients who will be treated with dexamethasone at 12 mg on 
Days 2-5 was not stopped early due to lack of efficacy of rolapitant and TerSera 
consents to continuation of the trial, the trial will proceed to the second part of the trial. 
 


Page 11 of 23 
October 28, 2019  
 
Treatment Plan: 
All patients will receive anti-emetics approximately 1- 2 hrs prior to chemotherapy 
infusion as follow:  Dexamethasone IV daily for 5 days (12 mg on days 1-5, after the 
amendment 2),  Ondansetron (5HT3 receptor antagonist) 16 mg IV daily for 5 days as 
standard of care, and Rolapitant, 180 mg will be administered PO on Day 1. For 5-days 
Ifosfamide regimen, the anti-emetics will be given for 6 days.  
 
Part II: This part will be a randomized, 2-arm phase II study of rolapitant vs 
fosaprepitant. If the trial was not stopped early, then the trial will proceed to the second 
part.  
 
Assuming 40% and 11% CR rates in Arm A, and Arm B respectively, approximately 78 
evaluable subjects will be randomly assigned to receive Rolapitant or fosaprepitant (1:1) 
administered as a single dose. The fosaprepitant arm will be used as standard arm to 
prevent patient selection bias.  
 
Treatment Plan: 
Patients will be randomized into two treatment arms:  
Arm A/ investigational arm: single dose of rolapitant n=39. 
Arm B/ control arm: single dose of fosaprepitant, n=39. 
 
Arm A/ investigational arm: all patients (n=39) will receive anti-emetics approximately 1- 
2 hrs prior to chemotherapy infusion as follow:  Dexamethasone IV daily for 5 days (12 
mg on days 1-5),  Ondansetron (5HT3 receptor antagonist) 16 mg IV daily for 5 days as 
standard of care, and Rolapitant, 180 mg will be administered PO on Day 1. 
 
Arm B/control arm: all patients (n=39) will receive anti-emetics approximately 1- 2 hrs 
prior to chemotherapy infusion as follow: Dexamethasone IV daily for 5 days (12 mg on 
day 1, and 8 mg on days 2-5), Ondansetron (5HT3 receptor antagonist) 16 mg IV daily 
for 5 days as standard of care, and  Fosaprepitant 150 mg will be administered IV on 
Day 1.  
 
If patients don't achieve complete response to Fosaprepitant in cycle 1 in the control 
arm, they can be given 2 doses of fosaprepitant on days 1 and 4 in cycle 2. 
 
Breakthrough nausea/vomiting and concomitant Medications 
Patients may take the following agents for breakthrough nausea as needed:  
Ondansetron, Lorazepam, Diphenhydramine, and Promethazine.  
 
5.2 Chemotherapy  
AI Regimen: 
Ifosfamide:  A total dose of 10 g/m2 will be administered by IV bolus over 3 hours on 
days 1, 2, 3, 4 (2.5 g/m2/day); or on days 1, 2, 3, 4, 5 (2 g/m2/day).  
 
Doxorubicin:  25 mg/m2/day IV continuous infusion for 72 hours on days 1, 2, and 3, 
completing infusion on day 4 (total dose:  75 mg/m2). 


Page 12 of 23 
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Mesna:  For Ifosfamide over 4 days: Prior to ifosfamide (Day 1) - 500 mg/m2 (20% of 
ifosfamide dose) given simultaneously with ifosfamide and then daily continuous 
infusion (Days 1-4 completing infusion on day 4) – 1,500 mg/m2/day (60% of daily 
ifosfamide dose) for a total of 6 gm/m2. For Ifosfamide over 5 days: Prior to ifosfamide 
(Day 1) - 400 mg/m2 (20% of ifosfamide dose) given simultaneously with ifosfamide and 
then daily continuous infusion (Days 1-5 completing infusion on day 5) – 1,200 
mg/m2/day (60% of daily ifosfamide dose) for a total of 6 gm/m2.  The mesna infusion 
will complete 24 hours after the last dose of ifosfamide.  
 
Vincristine: 2 mg IV by rapid infusion (Day 1) may be given to the patients with 
sarcomas of small cell histology. 
 
The chemotherapy cycles will be repeated around every 3 weeks if ANC > 1,500/mm3 
and platelet count > 100,000/mm3 and the patient has recovered from any acute 
toxicities of chemotherapy.   
 
5.3 Supportive Care 
Hematopoietic growth factors will be administered as per standard of care. All 
chemotherapy and growth factors will be used from commercial sources. 
 
5.4 Dose Modifications 
Every attempt will be made to deliver a minimum of 1 cycle of AI chemotherapy to each 
patient on the AI regimen.  In the case of the specific adverse events related to 
chemotherapy, dose reductions of doxorubicin and/or ifosfamide may be carried out as 
per standard practice. 
 
5.5 Duration of Therapy:  
Cycle 1 will be considered as the study cycle.  
 
Patients can receive up to a total of 6 cycles of chemotherapy in the absence of 
progressive disease and intolerable toxicity related to the study drug. Patients can 
receive Rolapitant or fosaprepitant, whichever arm they were assigned originally, in 
subsequent cycles (cycles 2-6).  The patients will continue to report adverse events 
including nausea/vomiting in daily symptom record diary during cycles 2-6. In addition, 
the patients need to fill out the FLIE questionnaire (Appendix E) in cycle 1 (e.g. days  5 
and 10) to monitor the improvement in nausea/vomiting.  
 
Therapy will be continued for at least 1 cycle unless there is a rapid progression of 
disease, and for additional 5 cycles, if there is stable or responding disease and if 
unacceptable toxicity is not observed (maximum total 6 cycles). 
 
 
6.0  Pretreatment Evaluation 
 


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October 28, 2019  
 
• Standard History and Physical examination including weight and height. 
• Karnofsky performance status > 60% (PS appendix D)  
• Laboratory studies will include a CBC with differential, and platelet count,       
electrolytes and serum chemistries. 
• Serum beta hCG or urinary pregnancy test (when indicated).   
• All screening labs/pretreatment evaluations can be done within 30 days 
before registration. 
 
 
7.0  Evaluation During Study 
 
• Interim History and Physical examination including weight will be done before 
each cycle of chemotherapy. 
• Patients will report on daily symptom record diary the adverse events, the 
date of all emesis episodes, intensity of nausea, and rescue medications 
before and during study on days 1-10 of the first  cycle. Also, patients will 
report the functional evaluations of nausea and emesis according to 
Functional Living Index-Emesis (FLIE) scale in cycle 1 ( e.g. days 1, 5 and 
10) (26). In addition, the patients will continue to report on daily symptom 
record diary the adverse events while on study. 
• Serum electrolytes and chemistries will be performed prior to every cycle and 
as frequently as needed during the cycle to monitor the toxicity 
• Management of hypersensitivity to the study drug: Patients with allergic 
reactions can be symptomatically managed. All patients with grade 4 
hypersensitivity reactions (anaphylaxis) will be removed from the study.  
 
 
8.0  End of Study/Early Withdrawal 
 
At their last clinic visit on the study, standard History and Physical examination including 
weight will be documented. Laboratory studies will include a CBC with differential, and 
platelet count. 
 
 
9.0  Criteria for Response 
 
9.1 Response 
All patients who receive one dose of study drugs (Rolapitant and fosaprepitant) under 
this protocol will be evaluable for response and toxicity. 
 
9.2 The severity of nausea will be reported in patients diary using 4-point scale (Likert 
scale), as 0 (none), 1 (mild), 2 (moderate), and 3 (severe) during cycle-1 of 
chemotherapy. 
 
9.3 Response will be defined as 0-24 hours, 24-120 hours, 120-240 hours, and overall 
period. 


Page 14 of 23 
October 28, 2019  
 
 
Complete response (CR): No emetic episodes and no rescue medications. 
 
Complete control (CC): CR and no more than mild nausea. 
 
9.4 Toxicity: Toxicities will be graded using the Common Terminology Criteria   for   
Adverse Events v4.03 – CTCAE (see Appendix C).  Uncomplicated, severe, or life 
threatening neutropenia and thrombocytopenia are expected toxicities of the study 
chemotherapy regimen and as such will not be collected as adverse events in this 
study since the data is already captured through the PDMS/CORE. 
 
 
10.0 Criteria for Discontinuation from Treatment 
 
Patients may be discontinued from study treatment at any time.  Specific reasons for 
discontinuing treatment include the following: 
• Serious or life-threatening adverse event 
• Risk to patients as judged by the Investigator and/or Sponsor 
• Severe noncompliance with protocol as judged by the Investigator and/or Sponsor 
• Request of the patient  
• Patient becomes pregnant 
• Progressive disease 
• Investigator becomes aware of conditions or events that suggest a possible hazard to 
patients if the clinical study continues 
10.1 Discontinuation from Study 
Patients who discontinue from treatment will continue to receive follow-up assessments 
as part of the study unless they are discontinued from study by one of the following 
events: 
• Withdrawal of consent 
• Loss to follow-up 
• Death from any cause 
• Termination of the study 
 
 
11.0 Statistical Consideration and Sample Size 
 
Statistical Considerations and Analysis  
 
This is a phase II trial to study the treatment efficacy of rolapitant on nausea/vomiting in 
patients with sarcoma receiving multi-day chemotherapy with doxorubicin and ifosfamide 
regimen (AI). This trial will be carried out in two parts. The primary goal of the first part of 
the trial is to estimate the preliminary efficacy of rolapitant administered as single-dose 
on Day 1 by evaluating complete response (CR) rate in a single-arm setting. The primary 
objective of the second part of the trial is to establish the efficacy of rolapitant 


Page 15 of 23 
October 28, 2019  
 
administered as single-dose on Day 1 by evaluating CR rate in comparison with the 
efficacy of fosaprepitant administered as single-dose on Day 1. 
 
Design and sample size/power 
Part I: A single-arm phase II study of rolapitant administered as single-dose on 
Day 1 
We will assess the efficacy of rolapitant on nausea/vomiting by evaluating CR rate using 
the Simon’s Minimax 2-stage design (27). A patient will be considered as to have a CR if 
s/he does not experience chemotherapy related emesis and do not need rescue 
medication during cycle-1 following initiation chemotherapy. The primary endpoint is CR 
rate in cycle 1 (days 1-10). In our previous study, we observed 2 (11%) CRs among 18 
patients who were treated with the standard of care. Based on the data of the 19 patients 
currently enrolled into this study, 6 out of 19 patients (32%) experienced CR. Therefore, 
a CR rate of 11% or less is considered as clinically insignificant, while a CR rate of 32% 
or higher is considered as clinically significant.  When the probability of accepting an 
ineffective regimen (CR rate ≤ 11%) is 0.05 and the probability of rejecting an effective 
regimen (CR rate ≥ 32%) is 0.05, the Simon Minimax 2-stage design requires 24 patients 
in the first stage.  The drug will be rejected if no more than 2 responses are seen in the 
first stage.  Otherwise, another 18 patients will be accrued.  At the end of the trial, the 
drug will be rejected if no more than 8 responses are observed in a total of 42 evaluable 
patients (maximum accrual 47 patients; 42 evaluable, potential 10% drop out rate).  The 
trial will be stopped early 50% of the time, and the mean sample size of the trial will be 
33 if the true response rate is 11%. Accrual will be halted after the 24th patient is enrolled 
until 3 or more responses are seen in the first stage. 
Since there is no interaction between rolapitant and CYP3A4, the dose of dexamethasone 
will not be reduced  from 12 mg to 8 mg and will be kept constant at 12 mg on Days 2-5 
for Part 1 (Rolapitant), and Arm A (Rolapitant) of the Part 2 as stated in “Treatment Plan” 
section. After 9 patients were accrued to the first phase of Part I of the study with a dose 
of dexamethasone at 8 mg on Days 2-5, the protocol was amended to keep 
dexamethasone dose constant at 12 mg on Days 2-5. Up to date, 19 patients have been 
enrolled and treated with dexamethasone at 12 mg on Days 2-5 as a new cohort for the 
first stage of the Simon’s Minimax 2-stage design, additional 5 patients will be accrued 
and treated in the first phase of Part I of the study as soon as this amendment is approved 
by IRB. The same rules of the design aforementioned will be applied. 
Part II: A randomized, 2-arm phase II study of rolapitant vs fosaprepitant 
The decision to move on to Part II of this study will not depend on the results of the 
patients who have been treated with dexamethasone at 8 mg on Days 2-5. Rather, if the 
first part of the trial for the patients who will be treated with dexamethasone at 12 mg on 
Days 2-5 was not stopped early due to lack of efficacy of rolapitant, the trial will proceed 
to the second part of the trial. This will be a randomized, 2-arm trial of rolapitant 
administered as single-dose on Day 1 in patients with sarcoma receiving multi-day 


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October 28, 2019  
 
chemotherapy with Doxorubicin and Ifosfamide regimen (AI). Arm A patients will receive 
a single dose of rolapitant on Day 1; Arm B patients will receive a single dose of 
fosaprepitant on Day 1. The primary objective is to evaluate the effect of rolapitant on 
nausea/vomiting as compared to the effect of a single dose of fosaprepitant in cycle 1 
(days 1-10). Again, a patient will be considered as to have a complete response (CR) if 
s/he does not experience emesis and do not need rescue medication during cycle-1 
following initiation chemotherapy. The primary endpoint is CR rate in cycle 1 (days 1-10). 
The sample size for this part of the trial will depend on the CR rate observed in the first 
part of the trial. Table 1 shows sample sizes required for three presumably observed CR 
rates in the first part of the trial assuming that the CR rate in Arm B is 11%. For example, 
a total of 78 patients, 39 in each arm, will provide the study 80% power to detect the 
differences of CR rates between the two arms using a Fisher exact test with a 0.05 two-
sided significance level when the respective CR rates are 40% and 11% in Arm A, and B 
(15, 16). All patients that complete cycle-1 (days 1-10) of chemotherapy will be 
considered evaluable for the study. Patients that can’t complete cycle-1 of chemotherapy 
due to disease progression, treatment change, withdrawal of consent, or other reasons 
will be replaced with new patients (maximum accrual 86 patients; 78 evaluable, potential 
10% drop out rate) nQuery 7.0 was used for the sample size or power calculation. 
Table 1. Sample size needed per arm in testing difference in complete response rate 
during cycle-1  between Arm A and B, Fisher’s exact test with two-sided significance 
level of 0.05 and 80% power assuming the CR rate of Arm B is 11% 
CR rate in Arm A 
30% 
40% 
45% 
50% 
Sample size 
78 
39 
31 
24 
 
Analysis Plans 
Patients’ demographic and clinical characteristics at baseline will be summarized using 
descriptive statistics such as mean, standard deviation, median, interquartile range (IQR), 
frequency where appropriate. We will apply Student t-test/Wilcoxon test and Kruskal-
Wallis test/ANOVA to compare continuous variables between different patient group, and 
the chi-square test or the Fisher’s exact test to assess the association between two 
categorical variables (28).  
 
For the analysis of the primary endpoint of the first part of the trial, we will provide point 
estimate along with 95% exact confidence interval (CI) of CR rate. 
 
For the analysis of the primary endpoint of the second part of the trial, Fisher exact test 
will be used to test the difference of CR rates between the two arms. CR rates along with 
their 95% confidence intervals (CIs) will be estimated by study arm. We will use logistic 
regression model (28) to assess the effect of patient specific covariates, such as 
treatment group, gender, etc.  on the complete response. The secondary endpoints are 
the response rates in each of the time periods (0-24 hours, 24 hrs-120 hrs, and 120-240 
hours). Logistic regression models using generalized estimating equations (GEE) will be 


Page 17 of 23 
October 28, 2019  
 
used to fit the response data to take the intra-patient correlation into account and to 
compare the differences of the response rates between the two treatment arms and to 
evaluate the effects of the patient specific covariates(29). 
 
Toxicity data will be summarized by frequency tables for all patients and by treatment 
arm.  For the efficacy endpoint, intent-to-treat analysis will be applied to the eligible 
patients. For the toxicity endpoint, per-treated analysis will be used to include any patient 
who received the treatment regardless of the eligibility nor the duration or dose of the 
treatment received. 
 
If there are missing data, the reasons for missing data will be recorded, and missing-data 
mechanism will be checked. For data missing at random (MAR),  multiple imputation 
techniques implemented in SAS PROC MI procedure to handle missing data will be used. 
For data missing not at random (MNAR), methods that add an explicit model for the 
missing mechanism to the data model will be applied. 
 
The data from the patients who were treated with dexamethasone at 8 mg on Days 2-5 
(prior to amendment 2) will be analyzed separately and included in relevant reports. 
 
Randomization 
Randomization will be carried out via CORe.  
 
 
12.0 Data and Protocol Management 
 
Data will be collected and entered in PDMS/CORE by the research staff assigned to the 
study. 
 
12.1 Good Clinical Practice  
The conduct of the study will conform to the recommendations for clinical studies in 
human subjects as per the guidelines on “Good Clinical Practice”, [21 CFR Part 312 and 
ICH guidelines]. 
 
 
13.0 Serious Adverse Events  and reporting requirement 
 
13.1 Reporting Product Quality Complaints for Rolapitant 
Any written, electronic or oral communication that alleges dissatisfaction related to 
manufactured clinical drug product with regards to its manufacturing, testing, labeling, 
packaging, or shipping, must be reported by the sponsor-investigator or qualified 
designee to TerSera Call Center (tersera@medicalinfodept.com) within 1 working day of 
first becoming aware of the possible defect.  This report to TerSera may be made by 
telephone to the designated TerSera representative (1-844-334-4035) or by fax to the 
call center (1-913-451-6409).  The product and packaging components in question, if 
available, must be stored in a secure area under specified storage conditions until it is 
determined whether the product is required to be returned for investigation of the defect.  


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October 28, 2019  
 
If the product complaint is associated with an SAE, the SAE must be reported 
separately in accordance with the protocol, and the SAE report should mention the 
product quality complaint. 
 
13.2 Adverse Events  
An adverse event (AE) is any new, undesirable medical occurrence or change 
(worsening) of an existing condition in a subject that occurs during or after treatment, 
whether or not considered to be product related.  Therefore, adverse events are 
treatment-emergent signs or symptoms.  In this study, the following adverse effects are 
expected and will not be reported.  They will be summarized in the updated and final 
analysis.  Myelosuppression and its associated complications are part of the treatment 
of sarcoma with high dose AI.  Therefore, low blood counts and related complications 
such as infections, bleeding and hospitalizations due to myelosuppression will not be 
reported as severe adverse drug reactions related to Rolapitant. 
 
AEs will be collected from the time of informed consent to 30 days after last study drug 
administration.  AEs that occur before the first study drug administration, concomitant 
illnesses, which existed before study entry, but did not worsen during the treatment 
period and any pre-existing conditions are known as “pre-treatment AEs” and by 
definition are “unrelated” to study drug. All AEs, regardless of the source of identification 
(e.g., physical examination, laboratory assessment, electrocardiograms [ECG], reported 
by patient), must be documented. 
 
Each AE will be assessed by the Investigator with regard to the intensity.  
Intensity should be assessed in accordance with the Common Terminology Criteria for 
Adverse Events (CTCAE v.4.03, Appendix C). Attribution of adverse events (AE) to 
study treatment will be recorded as follows: 
• Related:  The AE is clearly related to the study treatment. 
• Possible Related: The AE may be related to the study treatment. 
• Unlikely Related: The AE is doubtfully related to the study treatment. 
• Unrelated: The AE is clearly NOT related to the study treatment. 
 
 
Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be 
monitored until the AE has resolved, any abnormal laboratory values have returned to 
baseline or stabilized at a level acceptable to the Investigator, until there is a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, 
or until the patient has died. 
 
13.3 Serious Adverse Events  
 
A serious adverse event is defined by regulatory agencies as one that suggests a 
significant hazard or side effect that occurs (at any dose) and results if the event: 
• is fatal 


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October 28, 2019  
 
• is life threatening (places the subject at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing  hospitalization 
(excluding those for study therapy, disease-related procedures, palliative or hospice 
care, or placement of an indwelling catheter, unless associated with other serious 
events) 
• is a persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
 
Important medical events that may not be immediately life threatening or result in death 
or hospitalization but that may jeopardize the subject or require intervention to prevent 
one of the outcomes listed above, or result in urgent investigation, may be considered 
serious.  Examples include allergic bronchospasm, convulsions, and blood dyscrasias.  
If the adverse event is sufficiently severe in the investigator’s judgment, the subject 
should be removed from treatment and a termination assessment performed.  The 
subject should be given appropriate care under medical supervision until symptoms 
cease.  
The relationship to study drug therapy should be assessed using the following 
definitions:  
 
Deaths: 
All deaths occurring on study must be reported. These include deaths within 30 days of 
the last investigational product dose and deaths up to the last formal follow-up 
observational period. In addition, any death, which occurs after the protocol has ended, 
but is felt to be related to the study drug, must be reported to the FDA. 
 
All serious adverse events will be reported to the University of Texas M.D. 
Anderson Cancer Center IRB within five working days of knowledge of the event. 
 
13.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
For any AE that is serious, associated with the use of the study treatment, and 
unexpected (defined as any term not listed in the expectedness section of the current 
Prescribing Information) additional reporting requirements are described below. These 
types of reports are referred to as (SUSARs). 
• If the SUSAR is fatal or life-threatening, associated with the use of the study 
treatment, and unexpected, Regulatory Authorities and Independent Ethics 
Committees (IECs) will be notified within 7 calendar days after the Investigator 
learns of the event. Additional follow-up (cause of death, autopsy report, and 
hospital report) information should be reported within an additional 8 days 
(15 days total).  
• If the SUSAR is not fatal or life-threatening but is otherwise serious, associated 
with the use of the study treatment, and unexpected, Regulatory Authorities and 
IECs will be notified within 15 calendar days after the Investigator learns of the 
event.  


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October 28, 2019  
 
The Institution will also provide annual safety updates to the Regulatory Authorities and 
IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 
 
13.5 Pregnancy 
Pregnancies occurring in a female patient or a female partner of a male patient and 
pregnancy outcomes must be reported within 24 hours to the Institution contact 
provided above. Elective abortions without complications should not be considered AEs 
unless they were therapeutic abortions. Hospitalization for normal delivery of a healthy 
newborn should not be considered an SAE. Spontaneous abortions should always be 
reported as SAEs. 
The Investigator should follow-up with the study patient or the female partner of the 
study patient until delivery or termination of pregnancy, even if the patient was 
withdrawn from the clinical study or the clinical study was completed. The Company will 
be informed of all pregnancy outcomes.   
 
13.6 Sponsor SAE and Pregnancy Reporting to TerSera  
Institution will forward all treatment emergent SAE reports (MedWatch or CIOMS I form) 
regardless of causality, to TerSera within 24 hours of completion of the final report. The 
institution will forward both final initial and follow-up versions of each SAE report.  The 
Institution will also provide reports for all pregnancies in the same manner. 
TerSera Contact Details 
• Email: tersera@medicalinfodept.com 
• Fax: 1.913.451.6409 
 
Investigators must report to the Institution any SAE occurring after the signing of 
informed consent until 30 days following last study drug treatment and within 24 hours 
of becoming aware of the event. 
 
 
14.0 Monitoring Plan: All protocol participants will be registered in CORE.  The 
principal investigator will be responsible for submitting SAE’s to the IRB.  SAE’s 
will be submitted to OPR and entered into CORE. 
 


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