Clinical trial NCT05041101
Conditions: Breast Inflammatory Carcinoma Recurrent Breast Inflammatory Carcinoma Stage IV Breast Inflammatory Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2021-12-21; Completion date: 2024-09-06
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase Ib/II trial tests the safety and side effects of grapiprant and eribulin and whether they work to shrink tumors in patients with inflammatory breast cancer that has spread to other places in the body (metastatic). Grapiprant is an anti-inflammatory drug that may prevent tumor growth. Eribulin may block tumor cell growth by stopping tumor cell division. Giving grapiprant and eribulin together may help to control the disease.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the safety and efficacy of grapiprant and eribulin combination treatment for the patient with metastatic inflammatory breast cancer (mIBC).

SECONDARY OBJECTIVES:

I. To determine objective response rate (ORR), % of the patients who achieve complete response (CR) or partial response (PR).

II. To determine the time to progression (TTP) of the proposed treatment. III. To determine the duration of response of the proposed treatment. (Phase 2 only) IV. To determine the time to first response of the proposed treatment. (Phase 2 only) V. To determine progression-free survival (PFS) of the proposed treatment. VI. To determine the overall survival (OS) of the proposed treatment. VII. To investigate the predictive biomarker of the proposed treatment.

EXPLORATORY OBJECTIVE:

I. To evaluate the changes in the tumor microenvironment after the proposed treatment.

OUTLINE:

Patients receive grapiprant orally (PO) twice daily (BID) on day 1-21 and eribulin mesylate intravenously (IV) over 5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then yearly for up to 5 years.

Arms: arm 1: Patients receive grapiprant PO BID on day 1-21 and eribulin mesylate IV over 5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Eribulin Mesylate intervention 2: Grapiprant
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_001.pdf: 
Product:  Grapiprant 
1 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2021-0077 
Protocol Title 
Phase Ib/II study of grapiprant (IK-007) and eribulin combination treatment 
for metastatic inflammatory breast cancer (mIBC) 
Protocol Version 
04 
Version Date 
11/22/2022 
Protocol PI 
Sadia Saleem 
Department 
Breast Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
157135 
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Product:  Grapiprant  
1 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
Protocol 2021-0077: Phase Ib/II study of grapiprant (IK-007) and eribulin 
combination treatment for metastatic inflammatory breast cancer (mIBC) 
 
 
Principal Investigator: Sadia Saleem, MD,  
 
Co-principal Investigators: Toshiaki Iwase, MD, PhD; Rachel Layman, MD; Vicente Valero, MD 
 
Collaborating Statistician: Ying Yuan, PhD 
 
Department/Program: Breast Medical Oncology/Morgan Welch Inflammatory Breast Cancer Research 
Program and Clinic 
 
Protocol Type: Standard Protocol 
 
Protocol Phase: Phase Ib/II 
 
Version Status: 4.0 
 
 
 
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Product:  Grapiprant  
2 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
2021-0077 Protocol Synopsis 
 
Title 
Phase Ib/II study of grapiprant (IK-007) and eribulin combination treatment for 
metastatic inflammatory breast cancer (mIBC) 
Protocol No. 
2021-0077 
Phase 
1b/2 
Sponsor 
IKENA Onvology 
Investigational 
Product 
IK-007 
Study 
Population 
Metastatic inflammatory breast cancer 
Primary 
Objectives 
• 
Determine the safety and efficacy of grapiprant and eribulin combination 
treatment for the patient with mIBC. 
Secondary 
Objectives 
• 
Determine objective response rate (ORR), % of the patients who achieve 
complete response (CR) or partial response (PR). 
• 
Determine the time to progression (TTP) of the proposed treatment. 
• 
Determine the duration of response of the proposed treatment (Phase 2 only) 
• 
Determine the time to first response of the proposed treatment (Phase 2 only) 
• 
Determine progression-free survival (PFS) of the proposed treatment 
• 
Determine the overall survival (OS) of the proposed treatment 
• 
Investigate the predictive biomarker of the proposed treatment 
Exploratory 
Objectives 
• 
Evaluate the changes in the tumor microenvironment after the proposed 
treatment 
Treatment 
Regimen 
IK-007 (administered orally) and eribulin (administered intravenously) 
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Product:  Grapiprant  
3 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Study Design 
In the phase Ib part, a safety lead-in to the phase II part, the three enrolled patients 
will initially start grapiprant with 300 mg BID every day and eribulin (1.4 mg/m2, 
day 1 and day 8 of every cycle). We will monitor DLT during the 1st cycle of the 
treatment. If we observe < 2/3 DLT, we will enroll 3 more patients. If we observe 
0 or 1/6 DLT, we will start phase II in that dose and roll over the patients to phase 
II. If we observe DLT ≥ 2/3 or 2/6 patients, we will de-escalate the dosing to 200 
mg BID. In de-escalation (200 mg cohort), if we observe < 2/3 DLT, enroll 3 more 
patients. If we observe 0 or 1/6 DLT, we will start phase II in that dose and roll 
over the patients to phase II. If we observe DLT ≥ 2/3 or 2/6 patients, we will stop 
the safety trial.  
 
For phase II, the same toxicities that are defined as DLT in phase Ib will be 
continuously monitored during the first cycle of treatment using the following 
safety rule: After the first 9 patients (including the first 6 patient rolled over from 
phase Ib part), if the grade 3/4 toxicity rate >30%, the investigators will inspect the 
totality of the safety data and potentially terminate the trial for safety. 
 
Phase II adopts the Bayesian optimal phase II (BOP2) design with the null 
hypothesis H0: CBR = 10% versus the alternative hypothesis H1: CBR = 30%. If 
the phase II part starts with 300 mg dosing, we will enroll 6 patients and evaluate 
the clinical benefit in 12 patients (including 6 patients from the phase Ib cohort). 
For the purpose of futility monitoring, the assessment window for CBR is 24 
weeks. If we observed 2 or more clinical benefits in 12 patients, we will proceed to 
enroll 13 patients and claim the study promising if we observed 5 or more clinical 
benefits in 25 patients. This design yields the power of 86% with the type I error of 
10%. 
 
Number of 
Patients 
Total: 25 patients  
Number of Sites 
1 site 
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Product:  Grapiprant  
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Key Inclusion 
Criteria 
• Male or female ≥ 18 years of age. 
• Is willing and able to provide written informed consent for the trial. 
• Has histological confirmation of breast carcinoma with a clinical diagnosis of 
IBC.  
• Any prior treatments will be allowed except eribulin and/or any EP2/4 inhibitor 
. 
• Has at least 2 weeks of untreated period from the previous treatment. 
• Any receptor status for ER/PR and HER2. But for HER2+ type, must has failed 
trastuzumab, pertuzumab, and T-DM1 treatment. 
• Has a measurable disease per RECIST v1.1 (only applies to phase II part). 
• Has a distant metastasis site or locoregional recurrence.  
• Is willing to provide fresh tumor tissue via tumor biopsy before the first dose of 
the study drug only if participant has a disease can be be safely accessed through 
a CT-guided/US-guided or percutaneous biopsy for multiple core biopsies 
judged by the investigator. 
• Performance status (PS) of 0-2 on the Eastern Cooperative Oncology Group 
(ECOG) performance scale. 
• Has adequate organ function as determined by the following laboratory values:  
• Left ventricular ejection fraction (LVEF) ≥ 50% by ECHO or MUGA scan. 
• Female patients must not be pregnant or breastfeeding and must be practicing a 
medically acceptable form of locally approved birth control, be sterile or post-
menopausal. Male patients should be using a medically acceptable form of birth 
control during the trial or be sterile. 
o Female patient: A female patient is eligible to participate if she is not 
pregnant, not breastfeeding, and at least one of the following conditions 
applies:  
 Not a woman of childbearing potential (WOCBP) 
OR 
 A WOCBP agrees to follow the contraceptive guidance during 
the treatment period and at least 6 months after the last dose of 
trial intervention and must refrain from breastfeeding for at least 
2 months after the last grapiprant treatment.  
 Additionally, WOCPB must have a negative urine pregnancy test 
no more than 7 days prior to starting treatment on-study. 
o Male patients: A male patient must agree to use contraception during the 
treatment period and for at least 6 months after the last grapiprant 
treatment and refrain from donating sperm during this period. 
•  Patient with known HIV including current or prior infection would be included 
if with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL and without a history of AIDS-
defining opportunistic infections 
 
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Product:  Grapiprant  
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Key Exclusion 
Criteria 
• 
Current chronic use of NSAIDs, COX-2 inhibitors. We will allow prior use of 
those agents if patients stop them at least 2 weeks before accrual. 
• 
Is currently participating in a study of an investigational anti-cancer agent or 
receiving concurrent anti-cancer therapy for metastatic disease. 
• 
Has a diagnosis of immunodeficiency, or is receiving chronic systemic steroid 
therapy or any other form of immunosuppressive therapy. 
• 
Uncontrolled hypertension is defined as a systolic blood pressure > 150 mmHg 
or diastolic blood pressure > 90 mmHg, with or without antihypertensive 
medications. 
• 
 Has a history of and/or active cardiac diseases. 
• 
Has preexisting neuropathy > Grade 2. 
• 
Patients with known hypersensitivity to halichondrin B and/or halichondrin B 
chemical derivative. 
• 
Has medical conditions requiring concomitant administration of strong 
CYP3A4 or P-glycoprotein inhibitors or inducers. 
• 
Potentially life-threatening second malignancy requiring systemic treatment 
within the last 3 years (i.e., patients with a history of prior malignancy are 
eligible if treatment was completed at least 3 years before entering the 
Treatment period and the patient has no evidence of disease) or which would 
impede evaluation of treatment response. Hormone ablation therapy is allowed 
within the last 3 years. Patients with history of prior early stage basal/squamous 
cell skin cancer or non-invasive or in situ cancers that have undergone 
definitive treatment at any time are eligible.  
• 
Any other previous malignancies (except for cervical in situ cancers treated 
only by local excision and basal and squamous cell carcinomas of the skin) 
within 5 years. 
• 
Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. 
• 
Active infection requiring systemic therapy. 
• 
Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
• 
Known active Hepatitis B or C. 
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Product:  Grapiprant  
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Dose Limiting 
Toxicity 
The DLT will be defined as any of the following be “probable,” “possible,” 
and “definite events occurring in the first 21 days (cycle 1): 
• Any Grade 3 hematologic toxicity with the following changes: grade 3 platelet 
count (< 50,000/mm3–25,000/mm3) with associated bleeding (without bleeding, 
grade 4 platelet count [< 25,000/mm3] will be defined as DLT); grade 3 
absolute neutrophil count (<1,000–500/mm3) that persists for 7 or more days 
despite of the use of the grown factor support or that is associated with fevers 
(febrile neutropenia). (Otherwise, grade 4 absolute neutrophil count [< 
500/mm3] will be defined as DLT.)  
• Hepatocellular injury is indicated by 3-fold or greater elevations above the 
ULN of ALT or AST in addition to the elevation of serum total bilirubin > 2 x 
baseline. In such cases, no other reason can be found to explain the 
combination of increased transaminases and total bilirubin such as viral 
hepatitis, preexisting or acute liver disease, or another drug capable of causing 
the observed injury (Hy’s Law).  For patients with liver metastasis, 6-fold or 
greater elevations above the baseline of ALT or AST in addition to the 
elevation of serum total bilirubin > 4 x baseline. 
• Grade 3 nausea or vomiting that does not improve to Grade 1 within 72 hours 
of initiating supportive therapy. 
• Any other non-hematologic grade ≥ 3 toxicity deemed to be related to the study 
drug that lasts 72 hours or more will be considered a DLT.   
• A grade ≥ 3 laboratory abnormality that is determined to be of no clinical 
significance by the investigators will not necessarily constitute a DLT.  
• Any death not clearly due to the underlying disease or extraneous causes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
                                                TABLE OF CONTENTS 
 
TRIAL SUMMARY.................................................................................................... 9 
 
OBJECTIVES & HYPOTHESIS .............................................................................. 9 
 
Primary Objective ................................................................................................... 9 
 
Secondary Objectives ............................................................................................. 9 
 
Exploratory Objective ............................................................................................ 9 
 
BACKGROUND & RATIONALE ............................................................................ 9 
 
Inflammatory breast cancer (IBC) ........................................................................ 9 
 
Pharmaceutical and Therapeutic Background .................................................. 10 
 
Preclinical and Clinical Trial Data ...................................................................... 10 
 
The rationale for the Trial and Selected Subject Population ........................... 12 
 
Study Endpoint ..................................................................................................... 13 
 
METHODOLOGY ................................................................................................... 13 
 
Outcomes ............................................................................................................... 13 
 
Entry Criteria ........................................................................................................ 13 
4.2.1 Inclusion Criteria .................................................................................................. 13 
4.2.2 Exclusion Criteria ................................................................................................. 15 
 
Study Design .......................................................................................................... 17 
 
Treatment Plan ..................................................................................................... 19 
4.4.1 Dose Selection ...................................................................................................... 19 
4.4.2 Dose Modification ................................................................................................ 20 
 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 28 
Acceptable Concomitant Medications ............................................................................ 28 
Prohibited Concomitant Medications ............................................................................. 28 
 
Rescue Medications & Supportive Care ............................................................. 29 
 
Subject Withdrawal/Discontinuation Criteria ................................................... 29 
 
Study Stopping Rules ............................................................................................ 30 
 
Criteria for Disease Control ................................................................................. 31 
4.9.1. Definition of Treatment Response ........................................................................ 31 
4.9.2. Response will not be considered evaluable in the following categories: .............. 31 
 
Follow Up after off treatment .............................................................................. 31 
 
Remote Procedures ............................................................................................... 32 
 
Outside Physician Participation During Treatment .......................................... 32 
 
Study Calendar ..................................................................................................... 34 
 
OTHER STUDY PROCEDURES ........................................................................... 38 
 
Informed Consent/Patient Registration .............................................................. 38 
 
Biomarker assessments ......................................................................................... 38 
Tumor Samples ............................................................................................................... 38 
Urine samples .................................................................................................................. 38 
Blood samples ................................................................................................................. 39 
Assays 39 
 
Safety Monitoring and Reporting ....................................................................... 40 
5.3.1 Adverse Event ....................................................................................................... 40 
5.3.2 Serious Adverse Event Reporting (SAE) .............................................................. 41 
5.3.3 Evaluating Adverse Events ................................................................................... 43 
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Product:  Grapiprant  
8 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
DRUG INFORMATION .......................................................................................... 43 
 
Grapiprant .............................................................................................................. 43 
 
Eribulin .................................................................................................................. 44 
 
STATISTICAL ANALYSIS PLAN ........................................................................ 47 
 
LABELING, PACKAGING, STORAGE, AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 50 
 
Investigational Product ........................................................................................ 50 
 
Packaging and Labeling Information ................................................................. 51 
 
Clinical Supplies Disclosure ................................................................................. 51 
 
Storage and Handling Requirements .................................................................. 51 
 
Returns and Reconciliation .................................................................................. 51 
 
DATA MANAGEMENT .......................................................................................... 51 
 
Data collection plan .............................................................................................. 51 
 
Data confidentiality plan ...................................................................................... 52 
 
REFERENCES .......................................................................................................... 53 
 
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Product:  Grapiprant  
9 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 TRIAL SUMMARY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 OBJECTIVES & HYPOTHESIS 
 
Primary Objective  
To determine the safety and efficacy of grapiprant and eribulin combination treatment for the patient 
with metastatic inflammatory breast cancer (mIBC). 
 
Secondary Objectives 
(1) To determine objective response rate (ORR), % of the patients who achieve complete response 
(CR) or partial response (PR). 
(2) To determine the time to progression (TTP) of the proposed treatment. 
(3) To determine the duration of response of the proposed treatment (Phase 2 only) 
(4) To determine the time to first response of the proposed treatment (Phase 2 only) 
(5) To determine progression-free survival (PFS) of the proposed treatment 
(6) To determine the overall survival (OS) of the proposed treatment 
(7) To investigate the predictive biomarker of the proposed treatment 
 
Exploratory Objective 
To evaluate the changes in the tumor microenvironment after the proposed treatment 
 BACKGROUND & RATIONALE 
 
Inflammatory breast cancer (IBC) 
Definition of IBC 
Abbreviated Title 
Grapiprant for metastatic IBC 
Trial Phase 
Ib/II 
Clinical Indication 
Anti-inflammation therapy for metastatic IBC 
Trial Type 
Open-label, non-randomized, single-center  
Type of control 
None 
Route of administration 
Oral 
Trial Blinding 
No 
Treatment Groups  
One 
Number of trial subjects 
25 
Estimated duration of trial 
2-3 years 
Duration of Participation 
2 years 
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Product:  Grapiprant  
10 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
IBC is currently defined as diffuse erythema, edema (peau d’orange) of the breast, often without an 
underlying tumor mass, in the presence of pathologic evidence of breast cancer according to the 
clinical criteria outlined in the seventh edition of the AJCC Cancer Staging Manual of the American 
Joint Committee on Cancer [1]. Histologic evidence of dermal lymphatic invasion confirms the 
diagnosis but is not mandatory [2]. 
 
Metastatic IBC 
Although IBC accounts for a mere 2-6% of all breast cancers in the United States, IBC is responsible 
for a disproportionate 7% of breast cancer-related deaths [3-5]. Approximately 20% to 30% of 
patients with IBC present with distant metastasis at diagnosis (de novo metastasis, classified as stage 
IV disease) [6-8], compared to 6% to 10% of patients with non-inflammatory breast cancer (non-
IBC) [9, 10].  
   We have tested the hypothesis that OS is worse in patients with IBC than in non-IBC among 
patients with distant metastasis at diagnosis (stage IV disease). Survival curves were compared 
among 1504 consecutive patients with stage IV breast cancer (IBC: 206; non-IBC: 1298) treated at 
our institution from 1987 through 2012. The Cox proportional hazards model was used to determine 
predictors of OS. IBC was associated with a shorter median OS time than non-IBC (2.3 years vs. 3.4 
years; P = .01, log-rank test). In a multivariate Cox model that included 1,389 patients, the diagnosis 
of IBC was a significant independent predictor of worse OS (hazard ratio = 1.4, P = .00). In summary, 
IBC is associated with shorter OS than non-IBC in patients with distant metastasis at diagnosis 
(unpublished data). These data support the prognostic impact of IBC among patients with stage IV 
breast cancer. 
 
 
Pharmaceutical and Therapeutic Background 
Inflammation is the key component for the biology of IBC. Compared with non-IBC, IBC 
overexpresses the PTGS2 gene, which encodes cyclooxygenase (COX)-2 [11, 12]. COX-2 is an 
enzyme that catalyzes the generation of eicosanoid products, and it mediates pain and inflammation. 
Overexpression of COX-2 in breast cancer correlates with a more aggressive breast cancer profile 
characterized by higher proliferation rates, larger tumors, higher pathologic grade, hormone receptor 
negativity, and HER2 overexpression [13, 14]. The production of COX-2, prostaglandin E2 (PGE2), 
is also upregulated in the primary IBC and metastatic regions [15]. Our study has shown that a 
significant association between IBC progression and the COX-PGE2 pathway [16]. IBC cells have 
higher levels of COX-2’s enzymatic products, PGE2 and PGF2α, than non-IBC cells. Also, high 
COX-2 expression in tumor specimens correlates with poor overall survival outcome (n = 44). 
Intriguingly, PGE promoted the expression of cancer stem-like markers in IBC cell lines. PGE2 and 
PGF2α increased the CD44+/CD24-/low population of SUM149 cells and ALDH1 activity. 
Moreover, inhibition of the COX-PGE2 pathway decreased cancer stem-like marker and 
mammosphere formation. Celecoxib treatment decreased ALDH1 activity and mammosphere 
formation of SUM149 cells. Thus, the COX-2-PGE2 inflammatory pathway is a potential target for 
IBC treatment.  
 
 
Preclinical and Clinical Trial Data 
         Preclinical Data (See Investigator’s Brochure for details)  
Grapiprant is an antagonist of the prostaglandin E2 prostanoid 4 (EP4) receptor. EP4 belongs to the 
prostanoid receptor sub-family, a class of seven-transmembrane G protein-coupled receptors. EP4 
is one of four E2 prostanoid receptors that bind to and are activated by the metabolite PGE2. COX-
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Product:  Grapiprant  
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
1 and COX-2 synthesize PGE2 from the fatty acid precursor arachidonic acid. PGE2 is a well-
described modulator of the immune response and can be both pro- or anti-inflammatory depending 
on the specific context. EP4, a high-affinity PGE2 receptor, and EP2, a related low-affinity PGE2 
receptor, predominantly mediate the anti-inflammatory and suppressive activities of PGE2. 
   The anti-tumor activity of Grapiprant as a single agent and combined with a mouse anti-CTLA4 
antibody was evaluated in the 4T1 mouse breast cancer model grown in BALB/c mice. Mice were 
inoculated subcutaneously in the right flank with 3 x 105 tumor cells. When tumors reached an 
average size of 100 mm3 (7 days after tumor cell inoculation), dosing was initiated. During dosing, 
the tumor growth kinetics in mice treated with grapiprant dosed at 15 mg/kg BID and anti-CTLA4 
were decreased relative to the vehicle-treated mice. Moreover, the tumor growth kinetics in mice 
treated with grapiprant and anti-CTLA4 combined was decreased relative to either agent when 
dosed alone. The mice tolerated each dosing regimen as indicated by an average increase in body 
weight in each cohort during the treatment period and after treatment was discontinued. After 
treatment was discontinued, mice treated with grapiprant at 15 mg/kg BID combined with anti-
CTLA4 demonstrated improved survival relative to either single agent alone. After monitoring the 
mice for 41 days after tumor inoculation, 9 of 10 mice were still alive. Only 1 out of 10 mice were 
treated with anti-CTLA4 as a single agent, and 2 out of 10 mice were treated with grapiprant were 
still alive 41 days after tumor inoculation.  
   Grapiprant was evaluated in various animal models to characterize its pharmacologic safety 
profile, and there were no nonclinical findings that would preclude testing of grapiprant in clinical 
trials. 
 
         Clinical Data 
Grapiprant has been evaluated in approximately 1000 humans in studies conducted in the United 
States comprising single-ascending dose and multi-ascending dose studies, a food-effect study, a 
safety evaluation study in elderly subjects with renal impairment, an endoscopic gastrointestinal 
safety study, and in two Phase II studies in patients with osteoarthritis pain. For the solid 
malignancy, two Phase 1 studies, ARYS-001 and ARYS-002, are ongoing: 
1) ARYS-001: Safety and Efficacy of Grapiprant in Combination with Pembrolizumab in Advanced 
or Progressive microsatellite stable (MSS)-colorectal cancer (CRC).  
ARYS-001 is a multicenter, open-label single-arm Phase 1b study designed to evaluate the 
safety and efficacy of grapiprant combined with pembrolizumab. Participants receive treatment 
with grapiprant and pembrolizumab during the Combination Treatment period. Each 21-day 
treatment cycle comprises 21 consecutive days of grapiprant treatment and a single dose of 
pembrolizumab, administered on Day 1 of each cycle. Approximately 63 patients are planned to 
be screened for this study. Following the continuous safety assessment phase, 53 participants 
will be assessed to establish an estimate of efficacy. Cohort 1 enrolled participants at 300 mg 
BID, 450 mg every 12 hours (Q12h), 600 mg Q12h, and 900 mg Q12h before enrolling 
participants into Cohort 2. There have been no DLTs observed in the ARYS-001 study. 
 
2) ARYS-002: Safety and Efficacy of Grapiprant in Combination with Pembrolizumab in Advanced 
or Metastatic Post-PD-1/L1 non-small cell lung cancer (NSCLC) Patients.  
This study is an open-label, single-arm, Phase 1b/2 study designed to evaluate the safety and 
objective response rates in NSCLC subjects who have progressed on anti-PD-1 or anti-PD- L1 
therapy. A grapiprant dose of 300 mg BID was initially explored, and then, based on safety 
established in the ARYS-001 study, 900 mg every 12 hours (Q12h) has also been investigated. If 
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
the 900 mg Q12h dose is unsafe in this study, intermediate doses may be considered.. As of 
December 15, 2020, this study has been evaluating grapiprant 18 patients with NSCLC 
have been enrolled to date. Of the 18 subjects enrolled, 4 were treated with 900 mg q12h 
and 14 were treated with 300 mg BID of grapiprant in combination with a single dose of 
pembrolizumab. The 900 mg q12h dose level was not well tolerated in the 4 patients 
treated. One patient experienced a dose limiting toxicity and the 2 other patients 
withdrew due to hepatic toxicity events. After review of the safety data and discussion 
with the Investigators, the 900mg q12 dose level was deemed not tolerable.  
Additionally, while the 300 mg BID dose was well tolerated, there was no efficacy 
observed in 12 evaluable subjects. Based on the totality of the data, Ikena Oncology has 
decided to not explore further lower doses of grapiprant in combination with 
pembrolizumab in patients with NSCLC and  is terminating the  study ARYS-002. There 
are no subjects on study drug at this time and the follow-up period of the study has been 
completed. A clinical study report will be written and provided to the FDA as soon as 
available.  
  
   Among the SAEs currently reported for the two ongoing oncology studies, 8 SAEs were reported 
by 6 subjects related to the investigational drug as assessed by the investigator. The preferred terms 
of myositis and colitis were reported as treatment-related SAEs in Study ARYS-001. In Study 
ARYS-002, the preferred term of colitis was reported, and there were 2 SAEs reported related to 
liver abnormalities. The subject who experienced hepatic failure also reported treatment-related 
SAEs of hyponatremia and confusion. A previously reported SAE of intermittent junctional 
tachycardia occurred twice after treatment with grapiprant in the patient who had a prior history of 
arrhythmia-related to grapiprant. 
 
 
The rationale for the Trial and Selected Subject Population  
The prognosis for metastatic breast cancer (MBC) patients is poor, with an estimated 5-year survival 
of only 26%. Distant metastasis remains the main cause of death in patients with breast cancer despite 
important medical advances [17]. Therefore, MBC remains the most challenging task facing both 
cancer researchers and oncologists. IBC is associated with younger age at diagnosis, premenopausal 
status, African American race, more advanced disease stage, higher grade, high mitotic indices, 
family history of breast cancer, BRCA1 mutations, and more aggressive behavior than other breast 
cancer subtypes [4, 18]. To date, no IBC-specific targeted therapeutic options exist for the treatment 
of mIBC. Unfortunately, the median survival is only 2.3 years indicating that all patients will not 
maintain disease control after achieving a clinical response to systemic chemotherapy or endocrine 
therapy. The median survival is only 2.3 years for IBC, indicating that all patients will not maintain 
disease control after achieving a clinical response to systemic chemotherapy or endocrine therapy. 
To date, no specific targeted therapeutic options exist for the treatment of mIBC [3, 19].  
   Given the preclinical findings and clinical trial results, EP4 inhibitor has the potential to be a 
treatment option for mIBC since the COX-PGE pathway has a major role in driving IBC 
progression. In summary, IBC is associated with upregulated COX2 and PGE2, which can promote 
tumor progression. The downstream receptor of the COX-PGE pathway, EP4, is a highly potential 
candidate of the druggable target for mIBC. Taken together, the previous safety and preclinical data 
provide the rationale for conducting a clinical trial using grapiprant in mIBC treatment.  
 
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Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
Study Endpoint 
This clinical trial aims to confirm the safety and efficacy of grapiprant and eribulin mesylate 
(eribulin) combination treatment in patients with mIBC. The safety endpoint is dose-limiting toxicity, 
and the efficacy endpoint is the clinical benefit rate. We also aim to prove our concept that grapiprant 
modulates tumor microenvironment to an immune active status by conducting the correlative study. 
Also, we are going to evaluate the predictive biomarker of the proposed treatment. 
 METHODOLOGY 
 
Outcomes 
Primary outcomes 
• 
Dose-limiting toxicity (See section 4.4.2 Dose modification) 
• 
Clinical benefit rate (CBR): CR + PR + SD (>24weeks) 
 
Secondary outcomes 
• 
Overall objective response (ORR): % of the patients who achieve CR or PR. 
• 
Time to progression (TTP): the time from starting grapiprant treatment until objective 
tumor progression (PD). 
• 
Duration of response of the proposed treatment (Phase 2 only): the time from observing the 
response to the grapiprant treatment until objective tumor progression (PD) 
• 
Time to first response of the proposed treatment (Phase 2 only): the time from starting 
grapiprant treatment until observing the response. 
• 
Progression-free survival (PFS): the time from starting grapiprant treatment until objective 
tumor progression (PD) or death with any cause. 
• 
Overall survival (OS): the time from starting grapiprant treatment until death with any 
cause. 
• 
Association between the treatment response and the urine prostaglandin E2 metabolite in 
urine samples after the proposed treatment.  
 
Exploratory outcome 
• 
Change in 1) immune cell markers (M1/M2 macrophage, T lymphocyte, regulatory T cell, 
myeloid-derived suppressor cell, NK cell, dendritic cell, endothelial cell, fibroblast). 2) PD-
L1, PD-1, and ALDH1 on tumor and immune cells. 
 
Entry Criteria 
To be eligible for participation in this trial, the subject must meet the following criteria. 
4.2.1 Inclusion Criteria 
1. Male or female ≥ 18 years of age. 
2. Is willing and able to provide written informed consent for the trial. 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
3. Has histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on the 
presence of inflammatory changes in the involved breast, including diffuse erythema and edema 
(peau d’orange), with or without an underlying palpable mass involving the majority of the skin of 
the breast. Or the diagnosis confirmed by the MD Anderson IBC specialists. Pathological evidence 
of dermal lymphatic invasion should be noted but is not required for the diagnosis of IBC. 
4. Any prior treatments will be allowed except eribulin and/or any EP2/4 inhibitor . 
5. Has at least 2 weeks of untreated period from the previous treatment. 
6. Any receptor status for ER/PR and HER2. But for HER2+ type, must has failed trastuzumab, 
pertuzumab, and T-DM1 treatment. 
NOTE:  
HER2 positive status is defined as strongly positive (3+) staining score by IHC, 
or gene amplification using FISH, if performed. If IHC is equivocal (2+), please 
refer to Appendix H for current ASCO guidelines algorithm for evaluation of 
HER2.    
HER2 negative status, which is determined by assays using IHC require negative 
(0 or 1+) staining score. If IHC is equivocal (2+) staining score, please refer to 
Appendix H for current ASCO guidelines algorithm for evaluation of HER2.    
7. Has a measurable disease per RECIST v1.1 (only applies to phase II part). 
NOTE: 
Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one-dimension (longest diameter to be recorded) 
as ≥ 20mm by chest X-ray, ≥ 10mm by computed tomography (CT) scan, ≥ 10mm 
with calipers by clinical exam. 
Measurable malignant lymph nodes: To be considered pathologically enlarged 
and measurable, a lymph node must be ≥ 15mm in short axis when assessed by 
CT scan. 
Non-measurable disease: All other lesions (or sites of disease), including small 
lesions, are considered non-measurable. Bone lesions, leptomeningeal disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis, 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses [not followed by CT or 
magnetic resonance imaging (MRI)] are considered non-measurable. 
8. Has a distant metastasis site or locoregional recurrence.  
9. Is willing to provide fresh tumor tissue via tumor biopsy before the first dose of the study drug only  
if participant has a disease can be be safely accessed through a CT-guided/US-guided or 
percutaneous biopsy for multiple core biopsies judged by the investigator. If participant doesn’t have 
a disease that can be safely accessed, they are still eligible.   
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10. Performance status (PS) of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) performance 
scale. 
11. Has adequate organ function as determined by the following laboratory values:  
• 
Absolute neutrophil count (ANC) ≥ 1,200 /mcL 
• 
Platelets ≥ 100,000 /mcL 
• 
Hgb ≥ 9 g/dL 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (up to ≤ 3 x ULN for patients with 
liver metastasis) 
• 
ALT and AST ≤ 2.5 x ULN (up to ≤ 5 x ULN for patients with liver metastasis) 
• 
Cockcroft-Gault GFR (mL/min/1.73 m2) ≥ 50. Cockcroft-Gault GFR Creatinine 
Clearance Value = [(140-age) x weight (kg)]/(Scr x 72) (x 0.85 for females).  
 
12. Left ventricular ejection fraction (LVEF) ≥ 50% by ECHO or MUGA scan. 
13. Female patients must not be pregnant or breastfeeding and must be practicing a medically 
acceptable form of locally approved birth control, be sterile or post-menopausal. Male patients 
should be using a medically acceptable form of birth control during the trial or be sterile. 
o Female patient: A female patient is eligible to participate if she is not pregnant, not 
breastfeeding, and at least one of the following conditions applies:  
 Not a woman of childbearing potential (WOCBP) 
OR 
 A WOCBP agrees to follow the contraceptive guidance during the treatment period and at 
least 6 months after the last dose of trial intervention and must refrain from breastfeeding for 
at least 2 months after the last grapiprant treatment.  
 Additionally, WOCPB must have a negative urine pregnancy test no more than 7 days prior 
to starting treatment on-study. 
o Male patients: A male patient must agree to use contraception during the treatment period and 
for at least 6 months after the last grapiprant treatment and refrain from donating sperm during 
this period. 
 
14. Patient with known HIV including current or prior infection would be included if: 
• with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL 
• without a history of AIDS-defining opportunistic infections 
 
4.2.2 
Exclusion Criteria 
1. Current chronic use of NSAIDs, COX-2 inhibitors. We will allow prior use of those agents if 
patients stop them at least 2 weeks before accrual. 
2. Is currently participating in a study of an investigational anti-cancer agent or receiving concurrent 
anti-cancer therapy for metastatic disease. 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
3. Has a diagnosis of immunodeficiency, or is receiving chronic systemic steroid therapy or any other 
form of immunosuppressive therapy. 
4. Uncontrolled hypertension is defined as a systolic blood pressure > 150 mmHg or diastolic blood 
pressure > 90 mmHg, with or without antihypertensive medications. 
5.  Has a history of and/or active cardiac diseases. 
 History of cardiac diseases including: 
• 
active myocardial infarction documented by elevated cardiac enzymes or persistent 
regional wall abnormalities on assessment of left ventricular function. 
• 
history of documented chronic heart failure; and documented cardiomyopathy.      
Active cardiac diseases including: 
• 
symptomatic angina pectoris within the past 180 days that required the initiation of or 
increase in anti-anginal medication or other intervention. 
• 
ventricular arrhythmias except for benign premature ventricular contractions. 
• 
supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with 
medication. 
• 
conduction abnormality requiring a pacemaker. 
• 
valvular disease with documented compromise in cardiac function. 
• 
symptomatic pericarditis. 
 
6. Has preexisting neuropathy > Grade 2. 
7. Patients with known hypersensitivity to halichondrin B and/or halichondrin B chemical derivative. 
8. Has medical conditions requiring concomitant administration of strong CYP3A4 or P-glycoprotein 
inhibitors or inducers. 
9. Potentially life-threatening second malignancy requiring systemic treatment within the last 3 years 
(i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 3 
years before entering the Treatment period and the patient has no evidence of disease) or which 
would impede evaluation of treatment response. Hormone ablation therapy is allowed within the 
last 3 years. Patients with history of prior early stage basal/squamous cell skin cancer or non-
invasive or in situ cancers that have undergone definitive treatment at any time are eligible.  
10. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects 
with previously treated brain metastases may participate if they are stable and have no evidence of 
new or enlarging brain metastases. They are not using steroids for at least 28 days before trial 
treatment.   
11. Active infection requiring systemic therapy. 
12. Known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
13. Known active Hepatitis B or C. 
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Co-PI: Rachel Layamn 
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Study Design 
   The design of this study is a single-arm, phase Ib/II study. The overview of the study is shown in 
Figure 1. A total of 25 patients will be enrolled in the study. Once the recommended phase II dose 
of grapiprant in combination with eribulin is determined, the remaining patients will be treated in the 
phase II portion, which adds 14 ± 2 days window period of grapiprant treatment alone before the 
main study to evaluate the effect of grapiprant treatment in the tumor microenvironment and urine 
prostaglandin E2 metabolite. We will perform a correlative study by collecting tumor and urine 
samples at pre-and post-window periods. We will ensure the safety of grapiprant and eribulin 
combination by phase Ib part and determine efficacy in the phase II part—the detail of the trial design 
described in the statistical analysis plan (7.0).  
The starting dose of grapiprant will be 300 mg BID daily orally. Eribulin will be intravenously 
administered on day 1 and day 8 of every cycle (starting at the FDA-approved dose of 1.4 mg/m2). 
We define one cycle as 21 days. We will continue the treatment until disease progression, 
discontinuation by severe toxicity, death, and patient withdrawal. If the patients cannot continue the 
eribulin because of its toxicity, they will stop eribulin but continue grapiprant as a single treatment 
until progression or discontinuation. If the patients cannot continue the grapiprant because of its 
toxicity, they will be off treatment. We will follow-up with the patients up to 5 years after off-
treament (see section 4.9). The follow-up can be performed in the clinic in MD Anderson Cancer 
Center. If the patient is unwilling to come to the clinic, the follow-up would be done by phone. 
We will perform imaging analysis by PET-computed tomography (CT) or CT/bone scan at baseline, 
after the 2 cycles of proposed treatment (does not includes window period), then at the end of every 
3 cycles. The Quantitative Imaging Analyzing Core (QIAC) in MD Anderson Cancer Center will 
independently evaluate the treatment response based on the imaging results. 
 
 
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Figure 1. Overview of the trial design 
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Treatment Plan 
The dosing levels to be applied in this trial is outlined in Table 1 below. 
Table 1. Dosing level for grapiprant and eribulin in the phase Ib and II part 
 
*The dosing of 100 mg BID grapiprant will be used in phase II part only for the toxicity management. 
4.4.1 
Dose Selection 
The RP2D of Grapiprant is suggested as 300 mg BID (twice a day) from the ongoing phase I clinical 
trial for colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Those trials observed 
acceptable tolerability when it was combined with an immune-checkpoint inhibitor. The most 
frequent adverse event was liver toxicity (elevated GGP and ALP). Also, a G2/3 hepatic event was 
observed for 18.5% at 300 mg BID in the CRC study and 14.3% in the NSCLC study (See the 
investigator brochure). Base on the result from phase I trials, we will start the grapiprant from 300 
mg in phase Ib If we observe dose-limiting toxicity (DLT) with 300 mg BID, the dosing will go 
down to 200 mg BID and re-evaluate the safety (see the section of statistical analysis plan [7.0]). 
One cycle is defined as 21 days. Grapiprant will be administered orally every day of each cycle. A 
research medication diary will be used for source documentation. Patients will follow dosing 
instructions as below: 
 • Patients will take grapiprant daily as instructed dependent on their assigned dose.  Patients 
are encouraged to take study drug with food or within 2 hours after eating as food is known to 
decrease common mild gastrointestinal adverse events in drugs of a similar class (COX-2 
inhibitors). Patients are to maintain a normal diet. 
• 
Patients should take grapiprant every 12 hours at approximately the same time each day 
and evening, and not to take more or less than the prescribed dose at any time. 
• 
Patients should swallow the tablets whole and not chew, crush, or break them with about 8 
oz water. 
• 
The date, amount taken, and time of study drug administration will be recorded daily in a 
research medication diary.  
• 
If vomiting occurs, the patient should not take a replacement dose but should attempt to 
take their next scheduled dose if they are able. Any dose variations due to vomiting should be 
recorded on the research medication diary. 
Phase Ib (dosing level) 
Phase II (dosing level) 
Grapiprant 
(experimental) 
Eribulin 
(standard of care) 
Grapiprant 
(experimental) 
Eribulin 
(standard of care) 
300 mg BID, PO daily 
(0) 
1.4mg/m2, iv, day 1 
and day 8 (0) 
300 mg BID, PO daily 
(to be determined by 
phase Ib part) 
1.4mg/m2, iv, day 1 
and day 8 (0) 
200 mg BID, po daily (-
1) 
1.1mg/m2, iv, day 1 
and day 8 (-1) 
200 mg BID, po daily 
(to be determined by 
phase Ib part) 
1.1mg/m2, iv, day 1 
and day 8 (-1) 
 
0.7mg/m2, iv, day 1 
and day 8 (-2) 
100 mg BID, po daily*  
0.7mg/m2, iv, day 1 
and day 8 (-2) 
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• 
If the patient forgets to take a dose at the scheduled time, the patient can take the scheduled 
dose if less than 3 hours have passed from the regularly scheduled time. If more than 3 hours 
have passed after the scheduled time, then that missed dose should be omitted and the patient 
should continue treatment with the next scheduled dose. Any missed doses should be recorded 
in the research medication diary. 
Eribulin 1.4 mg/m2 will be administered on day 1 and day 8 of each cycle per institutional guidelines 
in the outpatient setting at MD Anderson or at the local clinic/hospital. The day 8 dose may be 
delayed for up to 1 week in patients with toxicities.  Please refer to Table 3 for recommended 
eribulin dose modifications and criteria for treatment interruption and re-initiation with treatment-
related adverse events. The toxicities requiring dose delays will be documented in the subject’s 
chart.  
4.4.2 
Dose Modification  
For patients who do not tolerate the protocol-specified dosing schedule, adjustments in 
grapiprant and eribulin doses are permitted to allow the patient to continue the study 
treatment. All dose modifications must be based on the worst preceding toxicity as graded 
by the NCI-CTCAE version 5.0. Those will also be counted as DLT when it meets DLT 
definition. The DLT will be defined as any of the following be “probable,” “possible,” and 
“definite events occurring in the first 21 days (cycle 1): 
• 
Any Grade 3 hematologic toxicity with the following changes: grade 3 platelet count (< 
50,000/mm3–25,000/mm3) with associated bleeding (without bleeding, grade 4 platelet count 
[< 25,000/mm3] will be defined as DLT); grade 3 absolute neutrophil count (<1,000–
500/mm3) that persists for 7 or more days despite of the use of the grown factor support or 
that is associated with fevers (febrile neutropenia). (Otherwise, grade 4 absolute neutrophil 
count [< 500/mm3] will be defined as DLT.)  
• 
Hepatocellular injury is indicated by 3-fold or greater elevations above the ULN of ALT or 
AST in addition to the elevation of serum total bilirubin > 2 x baseline. In such cases, no 
other reason can be found to explain the combination of increased transaminases and total 
bilirubin such as viral hepatitis, preexisting or acute liver disease, or another drug capable of 
causing the observed injury (Hy’s Law).  For patients with liver metastasis, 6-fold or greater 
elevations above the baseline of ALT or AST in addition to the elevation of serum total 
bilirubin > 4 x baseline. 
• 
All other grade 3+ electrolyte abnormality associated with clinical symptoms, regardless of 
duration. 
• 
Grade 3 nausea or vomiting that does not improve to Grade 1 within 72 hours of initiating 
supportive therapy. 
• 
Any other non-hematologic grade ≥ 3 toxicity deemed to be related to the study drug that 
lasts 72 hours or more will be considered a DLT.   
• 
A grade ≥ 3 laboratory abnormality that is determined to be of no clinical significance by the 
investigators will not necessarily constitute a DLT.  
• 
Any death not clearly due to the underlying disease or extraneous causes. 
Dose modification at the time of toxicities will be conducted as follows: 
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Grapiprant 
Safety management guidelines, including dose modification algorithms, are provided. Please note, in 
cases where the investigator is directed to permanently discontinue study treatment, these instructions are 
mandatory as described in this section. An overview of the available grapiprant dose modification 
guidelines is presented in Table 1. All AEs are to be graded according to NCI-CTCAE, version 5.0 
(http://ctep.cancer.gov). All dose modifications and the reason(s) for the dose modification must be 
documented in the eCRF. The major classes of grapiprant toxicity described in Table 2 include 
“Cardiac”, “Blood pressure”, and “Gastrointestinal”, “Renal”, and “Hepatic”.  
Investigators should refer to the grapiprant IB and Eribulin PI for additional information regarding the 
background of each drug and the management of other AEs or potential safety-related issues.   
   In case a dose reduction is necessary, the dose level or schedule of grapiprant may be changed as 
determined by the investigator and IKENA Oncology, consistent with the instructions for dose level and 
schedule (Table 2). If either study treatment is deemed intolerable and requires discontinuation despite 
optimal management, as described below, the participant must be discontinued from the study treatment, 
unless clinical benefit has been demonstrated. Any participant who requires a decrease in the grapiprant 
dose below 100 mg BID will discontinue grapiprant treatment and will come off study. Patients may 
continue to receive eribulin off study per standard of care if clinical benefit has been demonstrated per 
attending physicican discretion. Any participant that is required to discontinue eribulin for an AE may 
only continue on grapiprant if clinical benefit has been demonstrated and with agreement from the 
IKENA Oncology.  
   In the phase Ib part, we will set two dosing levels for grapiprant (300 mg and 200 mg). Grapiprant will 
start from 300mg BID daily and be initially tested in 3 patients. For the main study, we will set 2 dosing 
levels for grapiprant for dose reduction by the DLT in phase Ib part and 3 dosing levels for toxicity 
management in phase II part (Table 1). The major adverse events of grapiprant from previous clinical 
trials were not overlapped to those in eribulin; therefore, we will modify dosing based on the type of 
events. In the event of hepatic toxicity, we will modify the grapiprant first. The major reported adverse 
events for grapiprant from the phase I study include elevation of liver enzymes, colitis, myositis, and 
supraventricular tachycardia. The dosing modification for grapiprant will follow the instruction which is 
described later in this section. In case the patient had uncommon side effects, PI and clinical staff will 
discuss the event and determine which drug should be reduced dosing. the discussion of the event with 
the PI and the rationale (which drug to reduce) will be documented in the subject's chart. Table 2 
(grapiprant) and Table 3 (eribulin) show the summary of dose modification and criteria for treatment 
interruption and re-initiation. 
 
Table 2. Recommended grapiprant dose modifications and criteria for treatment interruption 
and re-initiation with treatment-related adverse events   
DOSE MODIFICATIONS FOR GRAPIPRANT  
Toxicity (CTCAE 5.0  
Grade)  
Grapiprant Dose Modifications  
Non-Hematologic Adverse Events Not Otherwise Specified 
Grade 1 
Administer symptomatic treatment as appropriate 
Continue study treatment at same dose  
 
Follow-up: 
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Symptoms resolve to baseline within 7 days:  
   Provide close follow-up to evaluate for increased severity.  
Symptoms ongoing >7 days:  
   Consider following algorithm for Grade 2 events. 
Grade 2  
Administer symptomatic treatment  
Investigate etiology  
Consider consulting subspecialist, biopsy, and/or diagnostic 
procedure  
Discuss with IKENA Oncology 
 
Follow-up: 
Symptoms ongoing >7 days or worsening  
• Consider interruption of study treatment  
• Resume study treatment at the same or lower dose if 
symptoms have improved to Grade 1  
• If potentially related to cumulative toxicity (past first cycle), 
consider changing administration of grapiprant to 2 weeks 
on/ 1 week off  
• If symptoms continue or worsen to Grade 3-4, follow 
algorithm for Grade 3-4 events 
Grade 3-4  
Interrupt or discontinue study treatment  
Consult sub-specialist  
Discuss with IKENA Oncology  
 
Follow-up: 
Symptoms improve to Grade ≤1:  
• 
Restart study treatment at a lower dose of grapiprant  
• 
If potentially related to cumulative toxicity (past first cycle), 
consider changing administration of grapiprant to 2 weeks 
on/ 1 week-off  
Symptoms ongoing:  
• Discuss further management with consultant and IKENA 
Oncology 
• Consider alternative therapy  
CARDIAC 
Arrhythmia (tachycardia: supraventricular tachycardia, atrial fibrillation) 
 
First Occurrence:  
Omit grapiprant 
Perform a repeat ECG within 1 hour of the first occurrence. 
Seek cardiologist input; address electrolytes, calcium, and 
magnesium abnormalities; concomitant medication must be 
reviewed. 
Second Occurrence:  
Permanently discontinue patient from grapiprant  
Other Cardiac Events  
Grade 1 or 2  
Continue study treatment at same dose 
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Grade 3  
Omit dose until resolved to ≤ Grade 1, then decrease 1 dose 
level 
Grade 4  
Permanently discontinue patient from grapiprant 
BLOOD PRESSURE 
Hypertension * true uncontrolled hypertension, not present at baseline, judged by the investigator to 
warrant a dose reduction 
Grade 1: systolic BP (sBP) 120-139 
mmHg or diastolic BP (dBP) 80-89 
mmHg 
Continue study treatment at same dose   
Grade 2: sBP 140-159 mmHg or 
dBP 90-99mmHg 
Omit dose until resolved to ≤ Grade 1  
Perform an ECG and seek cardiologist input per physician 
discretion; address electrolytes, calcium, and magnesium 
abnormalities; review concomitant medication.  
Once hypertension was resolved, the grapiprant may be restarted 
by decreasing 1 dose level. 
Continue measuring blood pressure daily at home. 
Grade 3:  sBP ≥ 160mmHg or dBP 
≥ 100 mmHg 
Omit grapiprant 
Perform an ECG and seek cardiologist input per physician 
discretion; address electrolytes, calcium, and magnesium 
abnormalities; review concomitant medication.  
Permanently discontinue patient from grapiprant 
GASTROINTESTINAL 
Colitis 
Grade 1  
Continue study treatment at same dose 
Grade 2  
Omit dose until resolved to ≤ Grade 1, then restart at the same 
dose.  
Persistent > Grade 2 regardless of 
etiology 
Permanently discontinue patient from grapiprant 
RENAL  
Serum creatinine   
< 2 x ULN   
Continue study treatment at same dose 
2–3 x ULN   
Omit dose until resolved to ≤ Grade 1, then resume  
HEPATIC  
Grade 1  
Administer symptomatic treatment as appropriate  
Continue study treatment at same dose  
 
Follow-up: 
Symptoms and laboratory abnormalities resolve to baseline 
within 7 days:  
   Provide close follow-up to evaluate for increased severity  
Symptoms or laboratory abnormalities ongoing >7 days:  
   Consider following algorithm for Grade 2 events  
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Grade 2  
Administer symptomatic treatment  
Monitor liver chemistries (ALT, AST, bilirubin) weekly until 
they resolve, stabilize or return to within baseline  
Investigate etiology  
Consider consulting subspecialist, biopsy, and/or diagnostic 
procedure  
Discuss with IKENA Oncology 
 
Follow-up: 
Symptoms or laboratory abnormalities ongoing >7 days or 
worsening:  
Consider interruption of study treatment  
• If interrupted, when symptoms and laboratory 
abnormalities have improved to Grade 1, resume study 
treatment at a lower dose of grapiprant (≤200 mg Q12h 
following the first dose reduction, and ≤100 mg Q12h 
following the second dose reduction)  
• With a second dose reduction, change administration of 
grapiprant to 2 weeks on/ 1 week off  
 
If symptoms continue or worsen to Grade 3-4, follow algorithm 
for Grade 3-4 events 
Grade 3  
Interrupt or discontinue study treatment  
Consult subspecialist  
Monitor liver chemistries (ALT, AST, bilirubin) at least twice 
weekly until they return to Grade 2, then follow Grade 2 
guidelines  
Discuss with IKENA Oncology  
 
Follow-up: 
Symptoms and laboratory abnormalities improve to Grade ≤1:  
• 
Resume study treatment at a lower dose of grapiprant 
(≤200 mg Q12h following the first dose reduction, and 
≤100 mg Q12h following the second dose reduction)  
• 
With a second dose reduction, change administration of 
grapiprant to 2 weeks on/ 1 week off  
  
Symptoms or laboratory abnormalities ongoing >7 days after 
Interruption:  
• 
Discuss further management with consultant and 
IKENA Oncology  
• 
Permanently discontinue study treatment  
Grade 4  
Permanently discontinue study treatment  
Monitor liver chemistries (ALT, AST, bilirubin) at least twice 
weekly until they return to Grade 2, then follow Grade 2 
guidelines  
Immediately inform IKENA Oncology and MD Anderson  
 
Follow-up: 
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Eribulin 
We will administer eribulin with 1.4mg/m2 on day 1 and day 8 in every cycle. We will assess eribulin's 
adverse reactions by obtaining the blood sample and physical examination, especially for peripheral 
neuropathy. We will not administer eribulin on day 1 or day 8 in patients with ≥ grade 3 neutropenia, ≥ 
grade 2 thrombocytopenia, or grade 3/4 nonhematologic toxicities. The day 8 dose may be delayed for up 
to 1 week in patients with toxicities. If toxicities resolve or improve to grade 2 or less by day 15, we will 
administer eribulin at a reduced dose and initiate the next cycle no sooner than 2 weeks later. If toxicities 
do not resolve or improve to grade 2 or less by day 15, we will omit the dose. If a dose has been delayed 
for toxicities that have recovered to the severity of grade 2 or less, resume the recommended reduced dose. 
If a dose has been reduced due to toxicities, we will not re-escalate. 
Table 3. Recommended eribulin dose modifications and criteria for treatment interruption and 
re-initiation with treatment-related adverse events   
Symptoms and laboratory abnormalities resolve to baseline 
within 7 days:  
   Provide close follow-up to evaluate for increased severity  
Symptoms or laboratory abnormalities ongoing >7 days:  
   Discuss further management with consultant and IKENA 
Oncology  
Management of Hepatotoxicity 
In the event of treatment-emergent hepatotoxicity, potential contributing factors such as concomitant 
medications, viral hepatitis and other infectious causes, choledocholithiasis, hepatic metastases, and 
myositis should be investigated. Concomitant medications or substances (eg, alcohol) known to be 
hepatotoxic which may be contributing to liver dysfunction should be discontinued or replaced with 
alternative medications to allow for recovery of liver function. As generally understood, AST or ALT 
>3x ULN and concomitant bilirubin ≥2.0 x ULN (>35% direct bilirubin), in the absence of elevated 
alkaline phosphatase or biliary injury, suggests significant liver injury. Liver dysfunction must be fully 
evaluated even if clinical signs and symptoms indicate progression of liver tumor lesions. Imaging 
studies must be obtained to document potential progression of malignancy. Report all Grade 4 and 
serious hepatotoxicity events to the IKENA Oncology within 24 hours. Complete liver event eCRF 
forms and SAE forms if the event also meets the criteria for SAE reporting. For dose reductions related 
to hepatotoxicity, the grapiprant dose will not exceed 200 mg Q12h following the first dose reduction, 
and 1000 mg Q12h following the second dose reduction, in addition to a change to a 2 week on/1 week 
off schedule for grapiprant with the second dose reduction. 
DOSE MODIFICATIONS FOR ERIBULIN  
Toxicity (CTCAE 5.0  
Grade)  
Eribulin Dose Modifications  
HEMATOLOGICAL  
 
Neutropenia (ANC)  
 
ANC < 500/mm3 for > 7 days or 
ANC < 1,000/mm3 with fever or 
infection 
Hold eribulin until ANC is ≥ 1,000 and platelet count is ≥ 75 x 
109/L, then decrease 1 dose level permanently 
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Product:  Grapiprant  
26 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Any event requiring permanent 
dose reduction while receiving 1.1 
mg/m2 
Hold eribulin until ANC is ≥ 1,000 and no fever, then decrease 
1 dose level  
Any event requiring permanent 
dose reduction while receiving 0.7 
mg/m2 
Discontinue eribulin 
Anemia (Hemoglobin) 
 
Grade 1 
Maintain dose level and continue eribulin with caution 
Grade 2 
Hold eribulin until hemoglobin is Grade 1.  
Grade 3-4 
Hold eribulin until hemoglobin is Grade 1, then decrease 1 dose 
level 
Thrombocytopenia (Platelet) 
Platelets < 25,000/mm3 or platelets 
< 50,000/mm3 requiring transfusion 
Hold eribulin until platelet (g/dL) is ≥ 100,000, then decrease 1 
dose level permanently 
Any event requiring permanent 
dose reduction while receiving 1.1 
mg/m2 
Hold eribulin until platelet (g/dL) is ≥ 100,000, then decrease 1 
dose level 
Any event requiring permanent 
dose reduction while receiving 0.7 
mg/m2 
Discontinue eribulin 
NEUROLOGICAL 
Peripheral neuropathy 
Grade 1  
Maintain dose level.  
Grade 2  
Omit dose until resolved to ≤ Grade 1, then restart at the same 
dose.  
Grade > 3  
Omit dose until resolved to ≤ Grade 1, then decrease 1 dose 
level.  
HEPATIC  
AST or ALT 
Grade 1 (> ULN–3.0 x ULN)  
Maintain dose level with liver function tests (LFTs)** 
monitored per protocol  
Grade 2 (> 3.0– 5.0 x ULN) without 
total bilirubin elevation to > 2.0 x 
ULN  
Omit dose until resolved to ≤ Grade 1, then  
-If resolved in ≤ 7 days, maintain dose level 
-If resolved in > 7 days, decrease 1 dose level 
Grade 3 (> 5.0– 20.0 x ULN)  
without total bilirubin elevation to > 
2.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then decrease 1 dose 
level  
Grade 4 (> 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN 
Permanently discontinue patient from eribulin 
AST and/or ALT and Albumin 
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Product:  Grapiprant  
27 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
Unanticipated Dose Interruptions  
AST and/or ALT > ULN–3.0 x 
ULN (grade 2) and albumin < LLN 
– 3 g/dL (grade 1) 
 
Omit dose until resolved to ≤ Grade 1, then  
-If resolved in ≤ 7 days, maintain dose level 
-If resolved in > 7 days, decrease 1 dose level 
 
AST and/or ALT > 3.0– 5.0 x ULN 
and albumin < 3 - 2 g/dL (grade 2) 
without total bilirubin elevation to > 
2.0 x ULN 
Permanently discontinue patient from eribulin 
Bilirubin (*for patients with Gilbert Syndrome these dose modifications apply to changes in direct 
bilirubin only) 
Grade 1 (> ULN–1.5 x ULN) 
Maintain dose level with LFTs** monitored per protocol  
Grade 2 (> 1.5– 3.0 x ULN) with 
ALT or AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then:  
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then decrease 1 dose level 
Grade 3 (> 3.0– 10.0 x ULN) with 
ALT or AST ≤ 3.0 x ULN 
Permanently discontinue patient from eribulin 
 
Dose Modifications for eribulin 
*Hepatic toxicity monitoring for patients with Gilbert Syndrome: total and direct bilirubin must be 
monitored, intensified monitoring applies to changes in direct bilirubin only; the monitoring includes 
the following LFTs: albumin, ALT, AST, total bilirubin, alkaline phosphatase. 
LFTs include albumin, ALT, AST, total bilirubin, alkaline phosphatase, and GGT  
- Cycle 1 and 2: every other week (if visit schedule allows more frequent monitoring, this should be 
considered) or more frequently if clinically indicated, especially for patients with borderline acceptable 
AST/ ALT/ bilirubin* values  
- Cycle 3 and onward: monthly or more frequently if clinically indicated  
In case of any occurrence of ALT/AST/ bilirubin* increase ≥ grade 2, LFTs must be monitored weekly 
or more frequently if clinically indicated until resolved to ≤ grade 1.  
In case of any occurrence of ALT/ AST/ bilirubin* increase ≥ grade 3 LFTs must be monitored weekly 
or more frequently if clinically indicated until resolved to ≤ grade 1; thereafter, the monitoring should 
be continued every other week or more frequently if clinically indicated. until the end of treatment with 
study medication  
Patients who discontinued treatment with eribulin should be monitored weekly, including LFTs* or 
more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE grade 
change over 4 weeks). 
All other AEs 
Grade 1 or 2  
Per physician discretion.  
Grade 3  
Omit dose until resolved to ≤ Grade 1, then decrease 1 dose 
level.  
Grade 4  
Permanently discontinue the patient from eribulin.  
Note: Omit dose for ≥ Grade 3 vomiting or Grade 3 nausea only 
if the vomiting or nausea cannot be controlled with optimal anti-
emetic treatment. 
Proprietary Information of MD Anderson


Product:  Grapiprant  
28 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's study record. Subjects 
who experience a recurrence of the same severe or life-threatening event at the same grade or greater 
with a re-challenge of grapiprant will be discontinued from trial treatment. 
 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations prohibited explicitly in the exclusion criteria are not allowed during the 
ongoing trial. If there is a clinical indication for one of these or other medications or vaccinations 
prohibited explicitly during the trial, discontinuation from trial therapy or vaccination may be 
required. The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician and will be documented in the subject's chart..  
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the investigator's discretion in keeping with the community standards of medical care. 
Concomitant medication will be recorded as the standard of care in the subject's medical record.  
Prohibited Concomitant Medications  
Subjects are prohibited from receiving the following therapies during the study.  
• 
NSAIDs, COX-2 inhibitors. 
• 
Any anti-cancer agents.  
• 
Radiation therapy. 
Note: Radiation therapy to the symptomatic solitary lesion will be allowed. The treatment 
will be continued during the treatment.  
• 
Live vaccines within 30 days before the first dose of trial treatment and while participating 
in the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chickenpox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines and are not allowed. Any mRNA vaccines for COVID-19 approved under an 
Emergency Use Authorization will be allowed in any case. 
• 
Subjects who, in the assessment by the investigator, require the use of any of the treatments 
mentioned above for clinical management should be removed from the trial. Subjects may 
receive other medications that the investigator deems to be medically necessary. There are 
no prohibited therapies during the post-treatment follow-up phase. 
Investigators should refer to the PI and associated addenda for complete details on the drug interaction 
potential of grapiprant. Highlights of drug interaction are summarized below. 
• 
Grapiprant is a p-glycoprotein substrate, however, it is unknown if Grapiprant is a substrate of 
CYP450 enzymes. Use of strong inhibitors and inducers of CYP3A4 and p-glycoprotein have been 
restricted in prior studies with Grapiprant. In this study, participants taking strong CYP3A4 or P-
Proprietary Information of MD Anderson


Product:  Grapiprant  
29 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
glycoprotein inhibitors or inducers are excluded from the study unless they can be transferred to 
other medications within ≥ 5 half-lives prior to dosing. 
• 
Concomitant use of drugs that are strong CYP3A inhibitors should be avoided (eg, aprepitant, 
clarithromycin, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, verapamil, 
and voriconazole). 
• 
Concomitant use of drugs that are strong CYP3A inducers should be avoided (eg, phenytoin, 
rifampin, carbamazepine, St John’s Wort, bosentan, modafinil, and nafcillin). 
• 
Grapiprant is not an inhibitor of CYP450 enzymes, but it is unknown if Grapiprant is an inducer of 
CYP450 enzymes. The exposure of drugs that are CYP450 substrates may be reduced by 
concomitant use of Grapiprant.  
• 
Concomitant use of drugs that are sensitive CYP450 substrates with a narrow therapeutic index 
should be avoided (e.g, warfarin, phenytoin, fentanyl). 
• 
Strong CYP2C8 inhibitors (eg, gemfibrozil) should be used with caution with grapiprant. 
 
Table 4: Examples of Narrow Therapeutic Index CYP450 Substrates  
 
 
 
Rescue Medications & Supportive Care 
There are no known rescue medications for the study treatments. Subjects should receive appropriate 
supportive care measures as deemed necessary by the treating investigator. Suggested supportive 
care measures for the management of adverse events are outlined below. 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 grapiprant or eribulin. It may be necessary 
to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography to evaluate 
the event. 
 
 
 
Subject Withdrawal/Discontinuation Criteria 
In this study, grapiprant administration will continue until one of the following conditions is 
observed. 
Narrow Therapeutic CYP 
substrate  
Examples 
CYP3A substrates  
alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus,  
CYP1A2 substrates  
theophylline, tizanidine  
CYP2C9 substrates  
warfarin, phenytoin  
CYP2C19  
s-mephenytoin  
CYP2D6 substrates  
thioridazine  
Proprietary Information of MD Anderson


Product:  Grapiprant  
30 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Disease progression [RECIST Criteria] 
Disease progression is defined as the rapid growth of multiple measurable, non-measurable, or new 
lesions, or at least a 20% increase in the sum of diameters of target (measurable) lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on the 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
Noncompliance:   
If the patient cannot be compliant with the treatment schedule in the absence of toxicity, the study 
treatment should be discontinued.  
Sustained side effects: 
Study treatment will be discontinued for patients who have sustained toxic effects attributed to the 
study drug and require a dose interruption lasting more than 12 weeks.  
Initiation of new anticancer treatment:   
In patients for whom the investigator determines new treatment for breast cancer is warranted in 
their judgment, the study treatment may be discontinued.   
Patient withdraws consent:  
If a patient withdraws consent, the reason(s) for withdrawal must be documented. Patients must be 
informed that their participation in the study is voluntary and that they may choose not to take part 
in the study or to stop taking part at any time. If a patient chooses not to take part in the study or 
discontinue at any time, his/her future medical care or medical benefits will not be affected.  
 
 
Study Stopping Rules 
We may terminate this study at any time after informing the IND office. Conditions that may 
warrant termination of the study include, but are not limited to the following: 
• 
Upon the emergence of an unexpected, serious, or unacceptable risk to the patients in the 
study. 
• 
Grade 3/4 toxicity rate > 30% (See details in section 7. STATISTICAL ANALYSIS 
PLAN ) 
• 
Upon the observation of the inefficacy in the phase 2 part. The BOP2 design in the phase 
2 part has an early stopping rule: if we observed less than 2 clical benefits in 12 patients, 
we will stop the study for futility. 
• 
A decision on the part of the IKENA Oncology to suspend or discontinue testing, 
evaluation, or development of the grapiprant. 
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Product:  Grapiprant  
31 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
 
Criteria for Disease Control 
This study aims to determine the safety and efficacy of grapiprant combination treatment in patients 
with mIBC. PI will be responsible for monitoring safety and disease control status. Detail of the 
adverse event and the evaluation of disease status will be documented and recorded in the study-
specific database.  
4.9.1. Definition of Treatment Response  
We will perform imaging analysis by CT scan, bone scan, or PET-CT. If the patient had a 
locoregional disease, a mammogram and ultrasound would be considered. We will evaluate the 
treatment response in metastasis sites (and primary site, if it exists) and at the following time 
points: 1) baseline 2) after 2 cycles of proposed treatment (does not include window period) 3) 
every 3 cycles of proposed treatment. All imaging analysis will be performed based on RECIST 
criteria. The efficacy outcomes will be CBR, ORR, Time to progression (TTP), Progression-free 
survival (PFS), and overall survival (OS).  
 
4.9.2. Response will not be considered evaluable in the following categories: 
Patients have to receive at least 2 cycles of the combination of eribulin and grapiprant to be 
evaluated the response. The patients in the following categories are considered to be unevaluable 
for the response. Those patients who are not evaluable will be excluded from the response's 
statistical analysis and not be replaced.  
Early Deaths:  
Patients who die within the first 2 weeks of the initiation of proposed treatment. These cases will 
be considered treatment failures. 
Lost to Follow-up:   
Patients for whom there is inadequate information to judge tumor response because of loss of 
contact with our institution (> 2 months after a missed appointment) and referring physician 
despite repeated attempts to locate them. These cases will be considered treatment failures in the 
intent-to-treat analysis. 
Major Protocol Violation:   
Patients who significantly deviate from the treatment program by either adding or deleting 
another agent or another therapeutic maneuver or modifying the schedule substantially (delay 
treatment ≥ 7 days without administration reason) of the drug under evaluation. Patients who do 
not fulfill the requirements outlined under patient eligibility are also included in this category.  
 Follow Up after off treatment 
30-day safety follow up 
The mandatory Safety Follow-Up should be conducted approximately 30 days after the last dose of 
the proposed treatment or before initiating a new anti-cancer treatment, whichever comes first. All 
Proprietary Information of MD Anderson


Product:  Grapiprant  
32 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
AEs that occur before the safety follow-up visit should be recorded. Safety follow-up can be done in 
the clinic or by phone if the patient cannot visit the clinic for follow-up.  
Patients who have an ongoing major study treatment related AE when the study treatment is 
completed or at discontinuation from the study will be followed up to 30 days until the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new anticancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or until it has 
been determined that study treatment or participation is not the cause of the AE.  
Survival Follow Up (yearly up to 5 years) 
The survival follow-up can be performed yearly for up to 5 years; if the patient is unable to visit the 
clinic, the follow-up will be done by chart review or by phone.   
 Remote Procedures  
In case of any unexpected incidents that patients can’t come back to MD Anderson Cancer Center 
for study treatment and assessments, remote procedures can be applied for this trial conduction, 
including remote consent, remote toxicity assessment via phone calls, virtual visit, etc., with 
compliance with institutional policies. Patients can have lab work, scheduled scans, physical exams 
and receive treatment locally if applicable. Laboratory work done at an outside facility is to be 
forwarded to the subject's attending physician at MDACC or the PI of the study, who will date and 
sign off on the labs to verify the results were reviewed. If the patient’s outside records are available 
to review in MDACC’s EMR ( i.e. EPIC ‘Care Everywhere’), then it will be documented in either 
the physician’s note and/or the  study coordinator’s note (attested by the physician) that the outside 
labs, infusions and other assessments were reviewed by the MDA attending physician. Remote 
monitoring can be applied as needed. Study drug may be mailed to the patient per institutional 
guidelines/approval.  
 Outside Physician Participation During Treatment 
1.  A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to participate in the patient's care (see Local Site Documents in ePRTCL). 
2.  Protocol required evaluations outside MDACC will be obtained by ‘Care Everywhere’ in EPIC, 
fax, or email. Records obtained via fax or email will be and scanned into the patient’s record.  
3.  Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator or their representative prior to initiation and documented in the patient record. 
4.  MDACC investigators will perform all decisions regarding dose adjustments and treatment 
interruptions or re-initiation of treatment, grading and attribution of adverse events, and assessment 
of efficacy. The home physician will not make any decisions regarding dose adjustments and/or 
treatment interruptions or resumption of treatment, grading and/or attribution of adverse events, or 
assessing efficacy. These will all be done by the MDACC investigators.  
5.  Routine, standard-of-care laboratory assessments (and physical exam when/if needed) will be 
performed by the home physician.  
6.  A copy of the informed consent and treatment schema will be provided to the local physician. 
Proprietary Information of MD Anderson


Product:  Grapiprant  
33 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
7.  Documentation to be provided by the local physician will include drug administration records, 
vital signs and progress notes, reports of the protocol required laboratory and diagnostic studies, and 
documentation of any hospitalizations.  Laboratory work done at an outside facility is to be forwarded 
to the subject's attending physician at MDACC or the PI of the study, who will date and sign off on 
the labs to verify the results were reviewed. 
8.  The local  physician will be requested to report to the MDACC physician investigator all life-
threatening events within 24 hours of documented occurrence. 
9. Eribulin will be administered on day 1 and day 8 of each cycle outpatient setting at MD Anderson 
or local clinic/hospital. 
 
Proprietary Information of MD Anderson


Product:  Grapiprant  
34 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 Study Calendar 
 
 
 
 
Treatment Cycles (1 cycle = 21 days) 
End of 
Treatment 
Post-Treatment 
 
Screening 
/Baseline 
 
Cycle 1 
Cycle 2 and beyond 
If patient 
returns for 
follow up   
30-days 
Safety F/U g 
 
 Survival 
Follow-Up h 
 
Wk 1 
Wk 2 
Wk 3 
 
Wk 4 
Wk 5 
Wk 6 
 
 
 
Scheduling Window (Days): 
Within 28 
days 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
30 days  
after the last 
dose 
Yearly, up 
to 5 years 
after off 
study 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
Grapiprant Administration (daily) 
 
x 
x 
x 
x 
x 
x 
 
 
 
Eribulin Administration 
 
x 
x 
 
x 
x 
 
 
 
 
Physical Exam a, PS a 
x 
x 
 
 
x 
 
 
x 
 
 
V/S 
x 
x 
x 
 
x 
x 
 
x 
 
 
Adverse Events a 
x 
x 
 
 
x 
 
 
x 
x 
 
Pregnancy Test – Urine or Serum β-HCG (for 
women with childbearing potential) j 
x 
 
 
 
 
 
 
 
 
 
Echo or MUGAd 
x 
 
 
 
 
 
 
 
 
 
EKGd 
x 
 
 
 
 
 
 
 
 
 
CBC  (with diff)  a 
x 
x 
x 
 
x 
x 
 
x 
 
 
CRP b, 
x 
 
 
 
x 
 
 
 
 
 
Biochemical Profiles, i, a 
x 
x 
 
 
x 
 
 
x 
 
 
CT scan and bone scan, or PET-CT. Breast 
MRI, mammogram and/or ultrasound per SOC. c 
x 
 
 
 
 
 
 
x 
 
 
Research tumor tissue Collection (metastatic 
site or primary site [if available]) e 
x 
 
 
 
x 
 
 
 
 
 
Research Blood/Urine Collection f 
x 
 
 
 
x 
 
 
 
 
 
Survival Status h 
 
 
 
 
 
 
 
 
 
x 
Table 5. Study flow chart  
a. Phase Ib 


Product:  Grapiprant  
35 
Protocol 2021-0077 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
a. Labs, PS and AEs will not be repeated if it was done within 8 (+/-3 days) days before starting treatment on Wk 1. PE at Wk 1 and day 1 of all 
subsequent cycles per physician discretion as clinically indicated 
b. C-reactive protein (CRP) will be obtained at baseline and at C2D1 (prior to treatment).   
c. As an evaluation of response, imaging analysis will be performed at baseline, after 2 cycles (C3) of proposed treatment (does not include window 
period), then at the end of every 3 cycles (C6, C9, C12, etc.). The other radiological evaluation may include ultrasound, bone scan, and X-rays, 
brain MRI, PET/CT, chest wall/breast photos as clinically indicated for a standard of care. 
d. ECHO, MUGA and EKG will be performed at baseline and as clinically indicated thereafter.    
e. Tumor tissue at the metastatic site or primary site (if available, exclude axillar lymph node) will be collected at baseline and  C2D1 (prior to 
treatment). If the patient had both primary and distant metastasis sites, we would collect sample from the primary site only (excluding axillar 
lymph node). The biopsy will be done by core needle biopsy, but punch biopsy will be considered if the primary site was a superficial disease. 
CT-guided biopsy or ultrasonography-guided biopsy will be used based on the location of the metastasis site. 
f. Peripheral blood and urine for correlative studies. Approximately 20 ml of blood (one 10 ml EDTA tube and one 10 ml Red top tube for the 
serum and PBMCs collection ) will be drawn at baseline and after C2D1 (prior to treatment).  . For the urine sample, we will collect 10 ml of 
sample in the urinalysis tube. Urine creatinine will be performed centrally at LabCorp from the frozen urine samples which will be shipped to 
them in batches. 
g. The mandatory Safety Follow-Up should be conducted approximately 30 days after the last dose of the proposed treatment or before initiating 
a new anti-cancer treatment, whichever comes first. All AEs that occur before the safety follow-up visit should be recorded. Safety follow-up 
can be done in the clinic or by phone if the patient cannot come to the clinic for follow-up.   
h. The survival follow-up will be performed yearly for survival status, up to 5 years, if the patient is unable to come to the clinic, the follow-up 
will be done by chart review or by phone. 
i.  Biochemical profiles/CMP (albumin, alkaline phosphatase, ALT, AST, LDH, GGT, uric acid, calcium, glucose, phosphorus, potassium, sodium, 
magnesium, total bilirubin, total protein, BUN, creatinine.   
j.   Screening Pregnancy test should be done within 7 days before the start of an initial regimen to be consistent with institutional policy 
CLN1114.     
 
 
 
 
 
 
 
 
 
 
 


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Protocol 2021-0077 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
b. Phase II: 
 
 
 
 
Treatment Cycles (1 cycle = 21 days) 
End of 
Treatment 
Post-Treatment 
 
Screening 
/Baseline 
 
 
Window 
period  
Cycle 1  
Cycle 2 and beyond 
If patient 
returns for 
follow up   
30-day 
Safety F/U g 
Survival 
Follow-Up h 
Wk 3 
Wk 4  
Wk 
5  
 
Wk 1  
Wk 2 
Wk 6 
Wk 7 
Wk 8 
 
 
 
Scheduling Window (Days): 
Within 28 
days 
 
 
 
 
± 3 
 
 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
30 days 
after the 
last dose 
Yearly, up 
to 5 years 
after off 
study 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Grapiprant Administration (daily)  
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Eribulin Administration  
 
 
 
x 
x 
 
x 
x 
 
 
 
 
Physical Exam a, PS a 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
V/S  
x 
 
 
x 
x 
 
x 
x 
 
x 
 
 
Adverse Events a 
x 
x 
 
x 
 
 
x 
 
 
x 
x 
 
Pregnancy Test – Urine or Serum β-
HCG (for women with childbearing 
potential) j 
x 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGAd 
x 
 
 
 
 
 
 
 
 
 
 
 
EKG d 
x 
 
 
 
 
 
 
 
 
 
 
 
CBC (with diff)  a  
x 
x 
 
x 
x 
 
x 
x 
 
x 
 
 
CRP b,  
x 
 
 
X 
 
 
 
 
 
 
 
 
Biochemical Profiles i, a 
x 
x 
 
x 
 
 
x 
 
 
x 
 
 
CT scan and bone scan, or PET-CT. 
Breast MRI, mammogram and/or 
ultrasound per SOC c 
x 
 
 
 
 
 
 
 
 
x 
 
 
Research tumor tissue Collection 
(metastatic site or primary site [if 
available]) e 
x 
 
 
x 
 
 
 
 
 
 
 
 
Research Blood/Urine Collection f 
x 
 
 
x 
 
 
 
 
 
 
 
 
Survival Status h 
 
 
 
 
 
 
 
 
 
 
 
x 


Product:  Grapiprant  
37 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
a. Labs, PS and AEs will not be repeated if it was done within 8 (+/-3 days) days before starting treatment on C1D1. PE per physician 
discretion as clinically indicated at C1D1 and day 1 of all subsequent cycles.  
b.  C-reactive protein (CRP) will be obtained at baseline and after the window period of proposed treatment.  
c. As an evaluation of response, imaging analysis will be performed at baseline, after 2 cycles (C3) of proposed treatment, then at the end of every 
3 cycles (C6, C9,C12 etc). The other radiological evaluation may include ultrasound, bone scan, and X-rays, brain MRI. PET/CT, chest 
wall/breast photos as clinically indicated for a standard of care 
d. ECHO, MUGA and EKG will be performed at baseline and as clinically indicated thereafter.    
e. Tumor tissue at the metastatic site or primary site (if available, exclude axillar lymph node) will be collected at baseline and after the window 
peroid (prior to C1D1 treatment). If the patient had both primary and distant metastasis sites, we would collect sample from the primary site 
only (excluding axillar lymph node). The biopsy will be done by core needle biopsy, but punch biopsy will be considered if the primary site was 
a superficial disease. CT-guided biopsy or ultrasonography-guided biopsy will be used based on the location of the metastasis site. 
f. Peripheral blood and urine for correlative studies. Approximately 20 ml of blood (one 10 ml EDTA tube and one 10 ml Red top tube for the 
serum and PBMCs collection) will be drawn at baseline and after window peroid (prior to C1D1 treatment). . For the urine sample, we will 
collect 10 ml of sample in the urinalysis tube. Urine creatinine will be performed centrally at LabCorp from the frozen urine samples which will 
be shipped to them in batches. 
g. The mandatory Safety Follow-Up should be conducted approximately 30 days after the last dose of the proposed treatment or before initiating 
a new anti-cancer treatment, whichever comes first. All AEs that occur before the safety follow-up visit should be recorded. Safety follow-up 
can be done in the clinic or by phone if the patient is unable to come to the clinic for follow up.   
h. The survival follow-up will be performed yearly up to 5 years for survival status, if the patient is unable to come to the clinic, the follow-up will 
be done by chart review or by phone. 
 i.  Biochemical profiles/CMP (albumin, alkaline phosphatase, ALT, AST, LDH, GGT, uric acid, calcium, glucose, phosphorus, potassium, sodium, 
magnesium, total bilirubin, total protein, BUN, creatinine. 
 j.   Screening Pregnancy test should be done within 7 days before the start of an initial regimen to be consistent with institutional policy 
CLN1114.


Product:  Grapiprant  
38 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 OTHER STUDY PROCEDURES 
 
Informed Consent/Patient Registration 
The study will be discussed with the patient, and any patient wishing to participate must give 
informed consent. A signed Institutional Review Board (IRB) approved, informed consent must be 
obtained from patients before any study-specific procedures or registration for study treatment can 
occur. All patients will be registered in the Clinical Oncology Research (CORe) system. 
 
Biomarker assessments 
In the phase Ib and II part, we will perform a correlative study to determine 1) change in the tumor 
microenvironment after grapiprant treatment by focusing on the immune cell population, PD-1/PD-
L1 expression, and ALDH expression in tumor cells. 2) the role of urine prostaglandin E2 metabolite 
as a biomarker for grapiprant treatment. A description of each assay is described below. 
Tumor Samples  
Collection 
Tumor tissue at the metastatic site or primary site (if available, exclude axillar lymph node) will be 
collected before therapy and after completing cycle 1 (phase Ib) and window period (phase II). If the 
patient had both primary and distant metastasis sites, we would collect sample from the primary site 
only (excluding axillar lymph node). The biopsy will be done by core needle biopsy, but punch 
biopsy will be considered if the primary site was a superficial disease. CT-guided biopsy or 
ultrasonography-guided biopsy will be used based on the location of the metastasis site. We will also 
collect urine and blood samples before therapy and after the completion of the window period. To 
ensure the obtained tissue samples include the highest possible proportion of tumor content, we will 
obtain 4 to 6 cores from the most representative lesions. Those tissues will be preserved by the 
formalin-fixed and paraffin-embedded (FFPE) form. The pre- and post-biopsy are mandatory both 
in phase Ib and II part (if applicable). Residual sample materials will be archived at the IBC lab and 
be available after completion of the designated assays. It may be used in the future for the 
identification of additional predictive markers or to enhance understanding of disease biology. In that 
case, we will obtain IRB approval before conducting additional assays. If biomarker samples are 
drawn but the study drug is not administered, samples will be retained.   
Evaluation 
We will determine the change in the tumor microenvironment that responds to the proposed treatment 
by multiplex staining. We will evaluate a population of immune cells (CD8+ T cell, CD4+ T-cell, B 
cell, Treg, Dendritic cell, and Macrophage [M1/M2]). Expression of PD-L1, PD-1, and ALDH1 on 
tumor and immune cells are also evaluated.  
Urine samples 
Collection 
   In the phase Ib and phase II part, we will collect a urine sample (phase Ib, before and after cycle 
1 treatment; phase II before and after window period). Urine collection is mandatory. The sample 
collection and processing will be as follows: 
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Product:  Grapiprant  
39 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
• 
A midstream urine sample should be collected in the clinic by having the patient void the first 
part into the toilet, then bringing the urine collection cup into the “midstream” to collect the 
urine sample. 
• 
The remainder of the urine may be voided directly into the toilet. 
• 
No part of the interior of the collection cup should be touched with the hands or any other part 
of the body. 
• 
Place urine sample on ice and prepare an aliquot from the urine sample immediately after the 
collection (no later than 30 minutes post-collection) to avoid any potential degradation. 
• 
Using a pipette, transfer at least 1mL of urine from the Urine collection cup into one (1) 10 
mL Urine Transport tube (white cap). 
• 
Immediately place transport tube on ice. 
• 
The urine transport tube should then be transferred from ice to frozen at ultra-low (-70 degrees 
Celsius +/- 10 degrees Celsius) as soon as possible. 
• 
 Urine creatinine will be performed centrally at LabCorp from the frozen urine sample shipped 
to them in batches. Discard the urine collection cup according to site regulations once the 
creatinine aliquot has been obtained. 
• 
Ship one (1) urine transport tube to Labcorp : 
ATTN: BioA Sample Management 
9211 Scicor Dr. 
Suite B, Door 19 
Indianapolis, IN 46214 
 
Blood samples 
Collection 
   We will collect 20 ml of blood before cycle 1 treatment and after completing the window period 
(both mandatory). The blood sample will be obtained in one 10 ml  EDTA tube and one 10 ml Red 
top tube for preserving serum and PBMCs. In the event a 10 ml EDTA or 10 ml red top is unavailable, 
the tubes may be substituted per institutional guidelines. The blood samples will be archived for 
future research related to this study. The future research will be a predictive biomarker investigation 
which includes comprehensive cytokine/chemokine analysis by serum and multiple immunoassays 
by PBMCs. Samples will be stored in IBC lab for 10 years, minimum. 
Assays 
We will investigate the immunological change in the tumor microenvironment to determine the 
immunomodulatory effect of grapiprant treatment. 
The multiplex immunostaining imaging and cytokine/chemokine assay (tumor tissue) 
Proprietary Information of MD Anderson


Product:  Grapiprant  
40 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
We will use multiplex immunostaining imaging (Akoya Biosciences) of FFPE or fresh samples for 
multiplex imaging analysis conducted routinely in our laboratory. In detail, we will quantify the 
following markers, which are known to be involved in tumor progression and therapeutic response: 
pan macrophage marker CD68; M2 markers CD163; T lymphocyte markers CD3 and CD8 regulatory 
T cell (Treg) markers FOXP3. The expression of PD-L1, PD-1, and ALDH1 on tumor cells will also 
be evaluated. Dr. Jangsoon Lee will perform the multiplex imaging analysis in the IBC lab. 
Urine prostaglandin E2 metabolite (PGEM, urine) 
We will determine the association between treatment response and the change in urine PGEM as a 
predictive biomarker. The assay will be performed at the laboratory in IKENA oncology. 
 
Safety Monitoring and Reporting 
5.3.1 
Adverse Event 
An Adverse Event is defined as any untoward medical occurrence in a patient regardless of its 
causal relationship to study treatment. An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study treatment, whether or not it is considered to be study 
drug(s) related. Included in this definition are any newly occurring events and any previous 
condition that has increased in severity or frequency since the administration of study. Adverse 
events will be captured from the time of the first protocol-specific intervention until 30 days after 
the last dose. 
Adverse events will be assessed according to the CTCAE version 5.0. All study patients who have 
received any dose of grapiprant will be evaluated for safety. Unexpected adverse events, including 
laboratory adverse events, deemed clinically significant by the investigator will be graded and 
recorded.  
Adverse Events Recording 
Adverse events will be captured in the study database REDCap. 
For Phase Ib and Phase II AEs ≥ 2 non-hematological and ≥ 3 hematological AEs occurring from 
the first dose of study treatment until 30 days after the last dose (or before initiating a new anti-
cancer treatment, whichever comes first)  observed by the investigator or reported by the subject 
(whether attributed to an investigational product) will be documented in the medical record and 
recorded in RedCap database. Baseline toxicities will be captured as part of the patient’s 
medical history, in the medical record/RedCap database. Abnormal laboratory values will not 
be reported as AEs; however,  the abnormal laboratory value is considered to be an AE if the 
abnormality:  
o Results in discontinuation from the study 
o Requires treatment, modification/interruption of study treatment dose, or any other 
therapeutic intervention  
o Is judged to be of significant clinical importance  
o If a laboratory abnormality is one component of a diagnosis or syndrome, then only 
the diagnosis or syndrome should be recorded on the AE page of the eCRF. If the 
Proprietary Information of MD Anderson


Product:  Grapiprant  
41 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
abnormality was not a part of a diagnosis or syndrome, then the laboratory 
abnormality should be recorded as the AE.  
 
 Events not included in the NCI CTCAE will be scored as follows: 
General grading: 
• 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required 
beyond prophylaxis. 
• 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
• 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment.  
• 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for subjects 
enrolled. 
5.3.2 Serious Adverse Event Reporting (SAE)  
5.3.2.1 Serious Adverse Event (SAE) Reporting Requirements for M D Anderson Sponsored 
Single Site IND Protocols 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• 
 Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 
CFR 312.32). 
Proprietary Information of MD Anderson


Product:  Grapiprant  
42 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
• 
Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
on Reporting Adverse Events for Drugs and Devices”. 
• 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug  unless the participant withdraws 
consent.  
• 
Serious adverse events must be followed until clinical recovery is complete and laboratory 
tests have returned to baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
• 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
• 
Death or life-threatening events that are unexpected, possibly, probably or definitely related 
to drug must be reported (initial or follow up) to the IND Office within 24 hours of 
knowledge of the event  
• 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
• 
The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office 
and MD Anderson IRB.  
• 
All events reported to the supporting company must also be reported to the IND Office 
5.3.2.2 Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor according to 21 CFR 
312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
5.3.2.3 Investigator Communication with Supporting Companies: 
The MDACC Internal SAE Report Form will be used for reporting to the IKENA oncology office 
(email: IITSafety@Ikenaoncology.com, FAX: 617-904-1802), and reporting timeline is as below: 
• 
Deaths that are unanticipated and definitely, probably, or possibly related to study 
intervention that occurs during and within 30 days after the last day of active study 
intervention will be reported to the IKENA oncology office within 24 working hours. 
Proprietary Information of MD Anderson


Product:  Grapiprant  
43 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
• 
All other SAEs that are serious, unanticipated, and definitely, or possibly related to study 
drugs will be reported to the IKENA oncology office within 2 working days.  
.  
 
• 
All SAEs and/or ECIs (events of clinical interest) from the time of treatment 
through 30 days following cessation of study treatment must be reported by the 
investigator and forwarded to Ikena periodically. 
 
• 
Pregnancy and Lactation  
Although pregnancy and lactation are not considered adverse events, investigators or their 
designees must report any pregnancy or lactation in a subject during the trial or within 120 
days of the study drug's last dose. Pregnancy outcomes of spontaneous abortion missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (the infant's health) must also be reported. 
Pregnancy report  submission is to be done via eSAE application as “Other Important 
Medical Event”. 
5.3.3 Evaluating Adverse Events 
An investigator or a designee will evaluate and record adverse events according to the NCI-
CTCAE version 5.0 as standard practice per institution guidelines.  
Attribution - the determination of whether an adverse event is related to a medical treatment or 
procedure.  
• 
Definite - the adverse event is clearly related to the investigational agent(s). 
• 
Probable - the adverse event is likely related to the investigational agent(s). 
• 
Possible - the adverse event may be related to the investigational agent(s). 
• 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
• 
Unrelated - The adverse event is clearly NOT related to the investigational agent(s). 
 
 DRUG INFORMATION 
 
Grapiprant 
Adverse reactions 
 
Liver Function Test Abnormalities 
Proprietary Information of MD Anderson


Product:  Grapiprant  
44 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
In the 2 phase I oncology studies, ARYS-001 and ARYS-002, treatment-emergent adverse events 
(TEAEs) of the liver > grade 2, including increased ALT, AST, transaminases, abnormal liver results, 
and hepatitis (elevated liver function tests), have occurred in 14/57 (25%) subjects on the study (10 
in ARYS-001 and 4 in ARYS-002) and have resulted in 7/57 (12.3%) subjects withdrawing from 
study treatment as a result of hepatic AEs. These events were all monitorable and resolved when 
study treatment was withheld. Other safety events continue to be assessed.  
GI Events 
There have been 2 GI events of colitis (3.5% of all subjects) reported as related to study treatment 
in the two ongoing Phase I oncology studies (ARYS-001 and ARYS-002) by patients receiving 300 
mg BID doses of grapiprant and 200 mg of pembrolizumab. Pembrolizumab is known to have colitis 
as a reported AE in approximately 3% of patients (Pembrolizumab package insert); however, 
grapiprant may also contribute to the frequency or severity of these events and thus will continue to 
be monitored. 
 
Cardiac Events 
In the ARYS-002 study, 1 subject with a diagnosis of NSCLC treated at 300 mg BID had a TEAE 
arrhythmia. This subject had a prior history of Intermittent Junctional Tachycardia that started at the 
initial diagnosis of the NSCLC. Two occurrences of junctional arrhythmia occurred on study within 
hours of taking grapiprant; the first on cycle 1, day 1 resulting in delayed grapiprant dosing and 
hospitalization for 24-hour observation with full recovery without pharmacologic intervention, and 
again on cycle 1, day 4 (second dose of grapiprant), with full recovery within hours without 
pharmacologic intervention. Both occurrences resulting in no change in blood pressure, no change 
in ECG interval lengths for PR, QRS, or QT segments and were deemed not life-threatening but 
prompted discontinuation by the investigator, who later deemed the event to be related to grapiprant. 
   A review of the safety databases across clinical development programs for grapiprant (ARY007) 
of MedDRA preferred terms of supraventricular tachycardia at that time (August 2019) revealed a 
total of 0 events reported in subjects treated to date with grapiprant up to 300 mg BID. A review of 
all potentially treatment-related cardiac events revealed a total of 9 events: 1 episode of sinus 
bradycardia; 1 episode of cardiac flutter; 2 episodes of palpitations; 2 episodes of vasodilation; 2 
episodes of prolonged QT interval, and 1 episode of ST-T change on ECG. As a result of these 
findings, blood pressure will continue to be monitored for early phase studies, and patients with a 
significant cardiac history will be excluded from enrollment. 
 
Events of Clinical Interest 
In addition to the events noted previously, one event of thrombosis, deemed by the investigator not 
to be related to study treatment, was reported as an event of clinical interest. The event was grade 3 
and resolved without sequelae. 
See the investigator brochure for detail on events of clinical interest defined for grapiprant . 
 
 
Eribulin 
The most common adverse reactions (≥ 25%) reported in patients receiving eribulin were neutropenia, 
anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most 
common serious adverse reactions reported in patients receiving eribulin were febrile neutropenia 
(4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of 
eribulin was peripheral neuropathy (5%). The adverse reactions described in Table 2 were identified 
in 750 patients treated in the previous clinical trial (EMBRACE trial).  In the study, patients were 
randomized (2:1) to receive either eribulin (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) or single-
agent treatment chosen by their physician (control group).  A total of 503 patients received eribulin 
and 247 patients in the control group received therapy consisting of chemotherapy (total 97% 
Proprietary Information of MD Anderson


Product:  Grapiprant  
45 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
[anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other 
chemotherapies 10%]) or hormonal therapy (3%). The median duration of exposure was 118 days 
for patients receiving eribulin and 63 days for patients receiving control therapy. Table 6 reports the 
most common adverse reactions occurring in at least 10% of patients in either group. 
Adverse reactions 
 
Cytopenias 
   Grade 3 neutropenia occurred in 28% (143/503) of patients who received eribulin in the 
EMBRACE trial, and 29% (144/503) of patients experienced grade 4 neutropenia. Febrile 
neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of 
febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients, 
and discontinuation was required in <1% of patients. The mean time to nadir was 13 days, and the 
meantime to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater 
thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating 
factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of 
patients who received eribulin.  
 
Peripheral Neuropathy 
   In the EMBRACE trial, 17% of enrolled patients had grade 1 peripheral neuropathy, and 3% of 
patients had grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy 
was required by 3% (14/503) of patients who received eribulin. Four percent (20/503) of patients 
experienced peripheral motor neuropathy of any grade, and 2% (8/503) of patients developed grade 
3 peripheral motor neuropathy.  
 
Liver Function Test Abnormalities 
   Among patients with grade 0 or 1 ALT levels at baseline, 18% of eribulin-treated patients 
experienced grade 2 or greater ALT elevation. One eribulin-treated patient without documented 
liver metastases had concomitant grade 2 elevations in bilirubin and ALT; these abnormalities 
resolved and did not recur with re-exposure to eribulin. 
 
Less Common Adverse Reactions 
The following additional adverse reactions were reported in ≥ 5% to < 10% of the eribulin-treated 
group: 
 
• Eye disorders: increased lacrimation 
• Gastrointestinal disorders: dyspepsia, abdominal pain, stomatitis, dry mouth 
• General disorders and administration site conditions: peripheral edema 
• Infections and infestations: upper respiratory tract infection 
• Metabolism and nutrition disorders: hypokalemia 
• Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness 
• Nervous system disorders: dysgeusia, dizziness 
• Psychiatric disorders: insomnia, depression 
• Skin and subcutaneous tissue disorders: rash 
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Product:  Grapiprant  
46 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Table 6. Adverse reactions with a per-patient incidence of at least 10% in the study 
 
 
 
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Product:  Grapiprant  
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Protocol 2021-0077 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 STATISTICAL ANALYSIS PLAN  
The design of the present study is phase Ib/II. Previous phase I clinical trial conducted in colorectal 
cancer and non-small cell lung cancer has established P2RD as 300 mg BID when grapiprant was 
combined with an immune checkpoint inhibitor. DLT was not observed in the group with 300 mg 
BID, and the most frequent adverse event was the elevation of liver enzymes. We expect that even if 
grapiprant was combined with eribulin, the combination treatment will be safely administered; 
however, we will start the combination from the phase Ib part to ensure safety. The decision of de-
escalation is described in Figure 2. The maximum sample size of this study is 25 patients. 
 
In the phase Ib part, a safety lead-in to the phase II part, the three enrolled patients will initially start 
grapiprant with 300 mg BID every day and eribulin (1.4 mg/m2, day 1 and day 8 of every cycle). We 
will monitor DLT during the 1st cycle of the treatment. If we observe < 2/3 DLT, we will enroll 3 
more patients. If we observe 0 or 1/6 DLT, we will start phase II in that dose and roll over the 
patients to phase II. If we observe DLT ≥ 2/3 or 2/6 patients, we will de-escalate the dosing to 200 
mg BID. In de-escalation (200 mg cohort), if we observe < 2/3 DLT, enroll 3 more patients. If we 
observe 0 or 1/6 DLT, we will start phase II in that dose and roll over the patients to phase II. If we 
observe DLT ≥ 2/3 or 2/6 patients, we will stop the safety trial.  
 
For phase II, the same toxicities that are defined as DLT in phase Ib will be continuously monitored 
during  the first cycle of treatment using the following safety rule: After the first 9 patients 
(including the first 6 patient rolled over from phase Ib part), if the grade 3/4 toxicity rate >30%, the 
investigators will inspect the totality of the safety data and potentially terminate the trial for safety. 
 
Phase II adopts the Bayesian optimal phase II (BOP2) design with the null hypothesis H0: CBR = 
10% versus the alternative hypothesis H1: CBR = 30%. If the phase II part starts with 300 mg 
dosing, we will enroll 6 patients and evaluate the clinical benefit in 12 patients (including 6 patients 
from the phase Ib cohort). For the purpose of futility monitoring, the assessment window for CBR is 
24 weeks. If we observed 2 or more clinical benefits in 12 patients, we will proceed to enroll 13 
patients and claim the study promising if we observed 5 or more clinical benefits in 25 patients. This 
design yields the power of 86% with the type I error of 10%. 
 
If the phase II part starts with 200 mg dosing, we will enroll 5 patients and evaluate the clinical 
benefit in 11 patients (including 6 patients from the phase Ib cohort). If we observed 2 or more 
clinical benefits in 11 patients, we will proceed to stage 2. For stage 2, (a) if 3 patients treated at 
300mg, we will enroll additional 11 patients, and we claim the study promising if we observed 4 or 
more clinical benefit in 22 (or 19) patients; and (b) if 6 patients treated at 300mg, we will enroll 
additional 8 patients and we claim the study promising if we observed 4 or more clinical benefit in 
19 patients. The power of the design is 86% and 82%, respectively in case (a) and (b), given the type 
I error of 10%.  The operating characteristics for the phase II portion of the trial are summarized in 
the Table 7 below: 
Table 7: The Operating Characteristics for Phase II 
Scenario 
 Clinical Benefit 
Rate 
Early Stopping 
(%) 
Claim 
Promising (%) 
Average Number of 
Patients (%) 
1 
0.1 
65.9 
8.3 
16.4 
2 
0.2 
27.5 
52.0 
21.4 
3 
0.3 
8.5 
86.4 
23.9 
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Product:  Grapiprant  
48 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
Scenario 
 Clinical Benefit 
Rate 
Early Stopping 
(%) 
Claim 
Promising (%) 
Average Number of 
Patients (%) 
4 
0.4 
2.0 
97.5 
24.7 
5 
0.5 
0.3 
99.7 
25.0 
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Product:  Grapiprant  
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Protocol 2021-0077 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Trial design for phase Ib/II of grapiprant and eribulin treatment 
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Product:  Grapiprant  
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Protocol 2021-0077 
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Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
The CBR and ORR will be summarized by frequency and percentage with 95% exact confidence 
intervals for all patients and by doses.  Time to progression (TTP), progression-free survival (PFS), 
and overall survival (OS) will be summarized using the Kaplan-Meier method, including median 
with 95% confidence intervals. 
 
For each exploratory outcome measure (see 6.2, Biomarker Assessments), samples will be acquired 
pre- and post-treatment. Change associated with treatment will be assessed by t-test and regression 
models with relation to treatment time, with adjustment for relevant demographic and baseline 
covariates.  A logistic regression model will be used to assess the association between objective 
response status and change in exploratory outcomes.  A proportional hazard model will be used to 
assess the association between TTP, PFS, and OS with the change in urine prostaglandin E2 
metabolite.  Additional statistical methods may be used. 
 
The Investigator is responsible for completing an efficacy/safety summary report and submitting it to 
the IND Office Medical Affairs and Safety Group, for review and approval. 
 
 Phase1b: 
After the first 3 evaluable patients complete 1 cycle of study treatment, and every 3 patients 
thereafter. IND Office approval must be obtained, prior to expanding/changing dose levels. 
 
Phase II: 
Toxicity summary will be submitted after the first 9 evaluable patients (including the 6 patients 
treated at MTD), then every 6 evaluable patients complete 1 cycle of treatment. 
 
Efficacy summary: 
If the MTD is 300mg, summary will be submitted after 12 evaluable patients (including the 6 
patients treated at MTD), complete 24 weeks of treatment and after the 25 evaluable patients 
complete 24 weeks cycles of treatment. 
 
If the MTD is 200 mg, Summary will be submitted after 11 evaluable patients (including the 6 
patients treated at MTD), complete 24 weeks of treatment, and after 25 evaluable patients complete 
24 cycles of treatment.  
 
A copy of the safety summary report should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 LABELING, PACKAGING, STORAGE, AND RETURN OF CLINICAL SUPPLIES 
 
Investigational Product  
   The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution, and usage of investigational product 
per the protocol and any applicable laws and regulations. Clinical Supplies will be provided by 
IKENA oncology as summarized in Table 7. 
Table 8. Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Grapiprant (100 mg) 
Oral Solid Dose Tablet, 50 count bottle 
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Product:  Grapiprant  
51 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
 
Packaging and Labeling Information 
   Clinical supplies will be affixed with a clinical label per regulatory requirements. 
 
Clinical Supplies Disclosure 
   This trial is an open-label; therefore, the subject, the trial site personnel, the designee are not 
blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
Storage and Handling Requirements 
   Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. An authorized person must record receipt and dispensing of trial medication 
at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
Returns and Reconciliation 
   The investigator is responsible for keeping accurate records of the clinical supplies received from 
IKENA oncology or designee, the amount dispensed to and returned by the 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 products will be destroyed at the site per institutional policy. 
The Investigator’s responsibility is 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. 
  DATA MANAGEMENT 
 
Data collection plan 
 Data collected from the study will be entered in RedCap/Prometheus. The Principal Investigator is 
responsible for assuring that the data entered into the database are complete and accurate and that 
data entry is performed promptly.  
Data collection for this study including: 
i. 
demographic information (sex, race, and date of birth). 
ii. 
physical information (weight and height)  
iii. 
date of initial breast cancer diagnosis, pathology report of primary breast cancer, biomarker 
status, and date and location of distant metastases. 
iv. 
date of disease progression, death. 
v. 
history of breast cancer surgery and radiation therapy, if applicable. 
vi. 
date and type of endocrine therapy, chemotherapy, and immunotherapy for metastatic disease. 
vii. 
all AEs will be collected; however, only ≥ 2 non-hematologic AEs and ≥ 3 hematological 
AEs will be recorded. Other abnormal laboratory values will not be reported as AEs; however, 
any clinical consequences of abnormality should be reported as AEs.  
Proprietary Information of MD Anderson


Product:  Grapiprant  
52 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
viii. 
Concomitant medication will be recorded per standard of care in the clinic database and not 
recorded in the study database.  
 
Data confidentiality plan 
   All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to patient 
identity will be possible only after accessing a password-protected database. Access to the database 
will be available only to individuals directly involved in the study. Information gathered for this study 
will not be reused or disclosed to any other person or entity or for other research. Once the research 
has been completed, identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point, they will be destroyed. 
 
 
 
Proprietary Information of MD Anderson


Product:  Grapiprant  
53 
Protocol 2021-0077 
PI: Sadia Saleem 
 
Co-PI: Rachel Layamn 
Date:  11/22/2022 
 
 
  
 
 
 
  REFERENCES 
1. 
Edge S, B.D., Compton C, AJCC Cancer Staging Handbook. 7th edition ed. 2010, New York: 
Springer. 
2. 
Dawood, S., et al., International expert panel on inflammatory breast cancer: consensus statement 
for standardized diagnosis and treatment. Ann Oncol, 2011. 22(3): p. 515-523. 
3. 
Anderson, W.F., et al., Epidemiology of inflammatory breast cancer (IBC). Breast Dis, 2005. 22: 
p. 9-23. 
4. 
Hance, K.W., et al., Trends in inflammatory breast carcinoma incidence and survival: the 
surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer 
Inst, 2005. 97(13): p. 966-75. 
5. 
Jaiyesimi, I.A., A.U. Buzdar, and G. Hortobagyi, Inflammatory breast cancer: a review. J Clin 
Oncol, 1992. 10(6): p. 1014-24. 
6. 
Wingo, P.A., et al., Population-based statistics for women diagnosed with inflammatory breast 
cancer (United States). Cancer Causes Control, 2004. 15(3): p. 321-8. 
7. 
Elias, E.G., et al., Long-term results of a combined modality approach in treating inflammatory 
carcinoma of the breast. Am J Surg, 1991. 162(3): p. 231-5. 
8. 
Curcio, L.D., et al., Beyond palliative mastectomy in inflammatory breast cancer--a reassessment 
of margin status. Ann Surg Oncol, 1999. 6(3): p. 249-54. 
9. 
Miller, K.D. and G.W. Sledge, Jr., The role of chemotherapy for metastatic breast cancer. Hematol 
Oncol Clin North Am, 1999. 13(2): p. 415-34. 
10. 
O'Shaughnessy, J., Extending survival with chemotherapy in metastatic breast cancer. Oncologist, 
2005. 10 Suppl 3: p. 20-9. 
11. 
Van Laere, S., et al., Distinct molecular signature of inflammatory breast cancer by cDNA 
microarray analysis. Breast Cancer Res Treat, 2005. 93(3): p. 237-46. 
12. 
Van Laere, S.J., et al., NF-kappaB activation in inflammatory breast cancer is associated with 
estrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK 
hyperactivation. Br J Cancer, 2007. 97(5): p. 659-69. 
13. 
Ristimäki, A., et al., Prognostic significance of elevated cyclooxygenase-2 expression in breast 
cancer. Cancer Res, 2002. 62(3): p. 632-5. 
14. 
Subbaramaiah, K., et al., Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: 
evidence for the involvement of AP-1 and PEA3. J Biol Chem, 2002. 277(21): p. 18649-57. 
15. 
Robertson, F.M., et al., Molecular and pharmacological blockade of the EP4 receptor selectively 
inhibits both proliferation and invasion of human inflammatory breast cancer cells. J Exp Ther 
Oncol, 2008. 7(4): p. 299-312. 
16. 
Wang, X., et al., EGFR signaling promotes inflammation and cancer stem-like activity in 
inflammatory breast cancer. Oncotarget, 2017. 8(40): p. 67904-67917. 
17. 
Lu, J., et al., Breast cancer metastasis: challenges and opportunities. Cancer Res, 2009. 69(12): p. 
4951-3. 
18. 
Bauer, K.R., et al., Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor 
(PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: 
a population-based study from the California cancer Registry. Cancer, 2007. 109(9): p. 1721-8. 
19. 
Dent, R., et al., Triple-negative breast cancer: clinical features and recurrence patterns. Clin 
Cancer Res, 2007. 13(15 Pt 1): p. 4429-34. 
 
Proprietary Information of MD Anderson

ICF_000.pdf: 
Protocol 2021-0077 
November 21, 2022 
Page 1 of 14 
 
 
Informed Consent 
 
 
 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN 
RESEARCH WITH OPTIONAL PROCEDURES   
 
Phase Ib/II study of grapiprant (IK-007) and eribulin combination treatment 
for metastatic inflammatory breast cancer (mIBC) 
2021-0077 
 
Subtitle: IK-007      
 
Study Chair:   Sadia Saleem 
 
_________________________ 
 
_____________________________ 
Participant’s Name 
 
 
 
Medical Record Number  
 
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary. 
 
This research has been reviewed and approved by an Institutional Review Board (IRB 
- a committee that reviews research studies). 
 
STUDY SUMMARY 
 
The goal of this clinical research study is to learn about the safety and effects of the 
combination of 2 different study drugs, grapiprant (also called IK-007) and eribulin, 
when given to patients with metastatic inflammatory breast cancer (mIBC). Metastatic 
means it has spread to other parts of the body. 
 
This is an investigational study. Grapiprant is not FDA approved or commercially 
available. It is currently being used for research purposes only. Eribulin is FDA 
approved and commercially available for the treatment of mIBC. It is considered 
investigational to give eribulin and grapiprant together to treat mIBC. 
 
The study doctor can explain how the study drugs are designed to work.  
 
The study drugs may help to control the disease. Future patients may benefit from 
what is learned. There may be no benefits for you in this study.  
 
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment.  


Protocol 2021-0077 
November 21, 2022 
Page 2 of 14 
 
 
You can read a full list of potential side effects below in the Possible Risks section of 
this consent. 
 
You may receive the study drugs until the disease gets worse or the study doctor 
thinks that it is no longer in your best interest. After that, you will be in follow-up for up 
5 years. You will no longer be able to take the study drugs if the disease gets worse, if 
intolerable side effects occur, or if you are unable to follow study directions. 
 
Grapiprant will be provided at no cost to you while you are on study. You and/or your 
insurance provider will be responsible for the costs of eribulin. 
 
You may choose not to take part in this study. Instead of taking part in this study, you 
may choose to receive standard chemotherapy, hormonal therapy, targeted therapy, 
or combination of these drugs if appropriate. The study doctor will discuss the possible 
risks and benefits of these treatments. You may choose to receive other 
investigational therapy, if available.  You may choose not to have treatment for cancer 
at all.  In all cases, you will receive appropriate medical care, including treatment for 
pain and other symptoms of cancer.   
 
1. STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this study. 
The following screening tests will help the doctor decide if you are eligible: 
• You will have a physical exam. 
• You will have an EKG and either a MUGA scan or an echocardiogram (ECHO) 
to check your heart function.  
• Blood (about 5 tablespoons) will be drawn for routine tests and for future 
biomarker research related to this study. Biomarkers are found in the 
blood/tissue/urine and may be related to your reaction to the study drugs.  
• Urine will be collected for routine and biomarker testing. 
• You will have imaging scans (chest x-ray, PET/CT, CT, MRI, mammogram, 
ultrasound, and/or bone scan) to check the status of the disease. The study 
doctor will tell you which imaging scans you may have.  
• You will have a biopsy to collect tumor samples for biomarker testing. The study 
doctor will tell you what kind of biopsy you will have. 
• If you can become pregnant, part of the above blood or urine sample will be 
used for a pregnancy test. To take part in this study, you must not be pregnant. 
 
The study doctor will discuss the screening test results with you. If the screening tests 
show that you are not eligible to take part in the study, you will not be enrolled. Other 
treatment options will be discussed with you. 
 
Study Groups 


Protocol 2021-0077 
November 21, 2022 
Page 3 of 14 
 
If you are found to be eligible to take part in this study, you will be enrolled in 1 of 2 
study groups (Group 1 or Group 2) based on when you enroll in the study. Group 2 will 
begin enrollment after Group 1 is complete.  
 
All participants will receive the same drugs at the same schedule, and the same dose 
of eribulin. However, Group 1 may receive 1 of 2 different doses level of grapiprant 
depending when they enroll in the study. The study doctor will tell you what dose of 
grapiprant you are receiving. 
 
Up to 25 participants will be enrolled in this study. All will take part at MD Anderson. 
 
Study Drug Administration 
Each cycle is 21 days.  
 
You will receive eribulin by vein over about 5 minutes on Days 1 and 8 of each cycle.  
 
You will take grapiprant by mouth 2 times every day or as instructed by your doctor 
with food or within 2 hours after eating. You should take your doses at about the same 
time every day. You should swallow the tablets whole with about a cup (8 ounces) of 
water. Do not chew, crush, or break the tablets.  
 
If you vomit a dose, do not take a replacement or “make up” dose. Wait and take your 
next dose as scheduled. 
 
If you are in Group 2, you will have a 14-day “pre-cycle” before the start of Cycle 1 in 
which you will take grapiprant alone for 2 weeks.  After the pre-cycle, you will begin 
taking both study drugs.  
 
Study Visits  
 
On Day 1 of each cycle: 
• You will have a physical exam. 
• Blood (about 1 tablespoon) will be drawn for routine tests. 
• You will have an EKG, if your doctor thinks it is needed. 
 
On Day 8 of each cycle, blood (about 1 tablespoon) will be drawn for routine tests.  
 
Before Cycle 2 (Group 1) or after the pre-cycle, but before the start of Cycle 1 
(Group 2): 
• Blood (about 2 tablespoons) will be drawn for future research. 
• Urine will be collected for biomarker testing. 
• You will have a core biopsy to collect tumor tissue for immune system and 
genetic testing, which may help researchers understand how the study drugs 
work in your body. 
 
Before Cycle 3 and then every 3 cycles after that (Cycles 6, 9, 12, and so on), you 
will have imaging scans to check the status of the disease. 


Protocol 2021-0077 
November 21, 2022 
Page 4 of 14 
 
 
End-of-Treatment Visit 
Within about 7 days after your last dose of study drugs: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine tests.  
• You will have imaging scans, if you have not had one in the last 3 cycles or if 
the doctor thinks you need one. 
 
Follow-Up 
About 30 days after your last dose of study drugs, and then 1 time every year after that 
for up to 5 years, you may be contacted (either by phone or in-person during an 
already-scheduled clinic visit) and asked about how you are doing and if you have 
started any new anti-cancer medications. If you are called, each call should last about 
2-5 minutes. The study staff may also review your electronic medical record every year 
for up to 5 years. 
 
Other Information 
While on you are on study, there are certain foods and drugs you should avoid. For 
example, avoid having any grapefruit and products containing grapefruit juice.  
 
It is very important that you tell the study doctor about any drugs you are taking or plan 
to take, including prescription and over-the-counter drugs, herbal supplements or 
remedies, corticosteroids, or vitamins/supplements.  
 
You cannot receive any live vaccine (such as FluMist®) within 30 days before your 
first dose of grapiprant and while on study. 
 
2. POSSIBLE RISKS 
 
While on this study, you are at risk for side effects. You should discuss these with the 
study doctor. The more commonly occurring side effects are listed in this form, as are 
rare but serious side effects. You may also want to ask about uncommon side effects 
that have been observed in small numbers of patients but are not listed in this form. 
Many side effects go away shortly after treatment is stopped, but in some cases side 
effects may be serious, long-lasting or permanent, and may even result in 
hospitalization and/or death. 
 
Side effects will vary from person to person, and some may occur after you have 
stopped receiving treatment. Tell the study staff about any side effects you may have, 
even if you do not think they are related to the study drugs/procedures. 
 
Grapiprant Side Effects 
 
This is an early study of grapiprant, so the side effects are not well known. 
Based on early human studies, grapiprant may cause: 
 


Protocol 2021-0077 
November 21, 2022 
Page 5 of 14 
 
• high blood pressure 
• fast/irregular 
heartbeat 
• high blood levels of 
sodium (possible 
weakness and/or 
swelling) 
• abdominal pain 
vomiting 
• inflammation of the 
intestines 
• stomach ulcers 
(sores) 
• diarrhea 
• abnormal liver tests 
(possible liver 
damage and/or 
yellowing of the skin 
and/or eyes) 
• abnormal kidney 
tests (possible kidney 
damage) 
 
Eribulin Side Effects 
 
Common (occurring in more than 20% of patients)       
 
Eribulin may commonly cause low blood cell counts (red blood cells and white blood 
cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or 
fatigue. You may need a blood transfusion.  
• A low white blood cell count increases your risk of infection (such as 
pneumonia and/or severe blood infection). Infections may occur anywhere and 
become life-threatening. Symptoms of infection may include fever, pain, 
redness, and difficulty breathing. 
 
Occasional (occurring in 3-20% of patients)      
 
• headache 
• loss of appetite 
• diarrhea 
• vomiting  
• abnormal liver tests 
(possible liver damage) 
• difficulty breathing 
• cough 
 
Exact frequency unknown but occurring in fewer than 10% of patients:  
 
• swelling (arm/leg) 
• depression 
• dizziness 
• difficulty sleeping 
• skin rash 
• low blood levels of 
potassium (possible 
weakness and/or 
muscle cramps)   
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• abdominal pain 
• upset stomach 
• abnormal taste 
• dry mouth 
• muscle spasms 
• teary eyes 
• infection 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• fatigue 
• fever  
• hair loss (partial or total) 
• nausea 
• constipation 
• weight loss  
• weakness  
• pain 
• nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function)  


Protocol 2021-0077 
November 21, 2022 
Page 6 of 14 
 
Eribulin may rarely cause a low platelet cell count. A low platelet count increases your 
risk of bleeding (such as nosebleeds, bruising, stroke, and/or digestive system 
bleeding). You may need a platelet transfusion.   
 
Using the study drugs together may cause side effects that are not seen when each 
is given alone. The study drug combination may also increase the frequency and/or 
severity of the side effects listed above. 
 
Other Risks 
 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or 
develop an infection with redness and irritation of the vein at the site where blood is 
drawn.  Frequent blood collection may cause anemia (low red blood cell count), which 
may create a need for blood transfusions. 
 
Having biopsies performed may cause pain, bruising, bleeding, redness, low blood 
pressure, swelling, and/or infection at the site of the biopsies.  An allergic reaction to 
the anesthetic may occur.  A scar may form at the biopsy site. 
 
EKGs/ECHOs may cause discomfort while lying on the exam table, and the tape on 
the EKG pads may cause skin irritation.  
 
MUGA scans may cause allergic reactions to the radioactive tracer, injection site 
soreness, and/or swelling. They may cause damage to cells or tissue from being 
exposed to the radiation used in the scan. These side effects may occur in less than 
10% of patients. 
 
During the MRI, you may feel mild vibrations throughout your body.  The machine will 
produce a loud knocking noise.  This is normal.  You will be given earplugs to protect 
your ears.  Some people, especially those who tend to feel uncomfortable in small or 
closed spaces, may feel “closed in” and become anxious while in the scanner.  The 
scanner has an intercom, which will allow you to speak to the staff during the 
procedure.  If you feel ill or anxious during scanning, tell the MRI staff and the 
scanning will be stopped if you wish.  The MRI will require a catheter to be inserted 
into one of your veins in order to inject the MRI contrast agent.  This may cause skin 
irritation, bleeding, and/or infection.   You may have an allergic reaction to the contrast 
agent. 
 
• abnormal EKG  
• low blood levels of 
magnesium (possible 
weakness, muscle 
cramps, and/or irregular 
heartbeat) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• dehydration 
• low platelet count 
• liver damage 
• lung inflammation 
(possible difficulty 
breathing) 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
• allergic reaction 


Protocol 2021-0077 
November 21, 2022 
Page 7 of 14 
 
The magnetic field used in MRI scanning may harm you if you have certain types of 
metal in your body (as might be found in pacemakers, neurostimulators, or certain 
clips). It may cause problems with devices, such as pacemakers. If you have metal in 
your body or devices such as a pacemaker, you should discuss this with the study 
doctor. 
 
CT scans send x-rays through the body at many different angles.  You will be 
exposed to a small dose of radiation.  All radiation adds up over a lifetime and may 
increase the risk of new cancer forming.  Some people may feel “closed in” while lying 
in the scanner.  However, the scanner is open at both ends, and an intercom allows 
you to talk with doctors and staff.  If you feel ill or anxious during scanning, doctors 
and/or radiology technicians will give comfort, or the scanning will be stopped.  
Solution may also be given by vein to make the x-ray pictures more accurate.  This 
may cause an uncomfortable feeling of warmth, nausea, and/or severe allergic 
reactions.  The solution injection may also cause pain, bleeding, bruising, hives, 
and/or itching. 
 
A PET scan may cause you to feel “closed in” while lying in the scanner. However, 
the scanner is open at both ends and an intercom allows you to talk with doctors and 
staff. If you feel ill or anxious during scanning, doctors and/or technicians will give 
comfort or the scanning will be stopped. 
 
The PET scan exposes your body to radiation. The radioactive solution does not 
remain in your system for a long period of time. However, you should wait 2 hours 
before holding an infant or getting close to a pregnant woman to avoid exposing them 
to radiation. You should drink fluids after the scan to help remove the solution from 
your system. 
 
X-rays send a small amount of radiation though the body. All radiation adds up over a 
lifetime and may increase the risk of a new cancer forming. 
 
A standard bone scan exposes you only to the radiation that comes from injecting the 
standard radioactive imaging solution for bone imaging. 
 
This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you 
should not become pregnant, breastfeed a baby, or father a child while on this study.  
 
If you can become pregnant or father a child and you are sexually active, you must 
use birth control during the study and at least 6 months after your last dose of study 
drugs. Effective methods of birth control include:  
• Use of hormonal birth control methods: pills, shots/injections, implants (placed 
under the skin by a health care provider), or patches (placed on the skin) 
• Intrauterine devices (IUDs) 
• Using 2 barrier methods (each partner must use 1 barrier method) with 


Protocol 2021-0077 
November 21, 2022 
Page 8 of 14 
 
spermicide. Males must use a male condom (latex or other synthetic material) with 
spermicide. Females must choose either a diaphragm with spermicide, or cervical 
cap with spermicide, or a sponge. 
 
Males: Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy. 
 
Females: If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant will result in your removal from this study.   
   
3. COSTS AND COMPENSATION  
 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson or IKENA Oncology for this 
injury. You may also contact the Chair of MD Anderson’s IRB at 713-792-6477 with 
questions about study-related injuries. By signing this consent form, you are not giving 
up any of your legal rights. 
 
Certain tests, procedures, and/or drugs that you may receive as part of this study may 
be without cost to you because they are for research purposes only. However, your 
insurance provider and/or you may be financially responsible for the cost of care and 
treatment of any complications resulting from the research tests, procedures, and/or 
drugs. Standard medical care that you receive under this research study will be billed 
to your insurance provider and/or you in the ordinary manner. Before taking part in this 
study, you may ask about which parts of the research-related care may be provided 
without charge, which costs your insurance provider may pay for, and which costs may 
be your responsibility. You may ask that a financial counselor be made available to 
you to talk about the costs of this study. 
 
Samples that are collected from you in this study may be used for the development of 
treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit. 
 
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research.  
 
You may receive some reimbursement for costs that are a direct result of your 
participation, such as travel expenses. You may receive up to a maximum of $100 
for hotel costs per visit (up to 6 times), you may receive up to a maximum of $15 for 
parking per visit (up to 6 times), for a total amount of up to $600.You will need to 
provide receipts for your expenses to be eligible for reimbursement. Please ask the 
study staff about this possible reimbursement. 
 


Protocol 2021-0077 
November 21, 2022 
Page 9 of 14 
 
 
Additional Information  
 
4. You may ask the study chair (Dr. Sadia Saleem, at 281-566-1900) any questions you 
have about this study. You may also contact the Chair of MD Anderson's Institutional 
Review Board (IRB - a committee that reviews research studies) at 713-792-6477 with 
any questions that have to do with this study or your rights as a study participant. 
 
5. You may choose not to take part in this study without any penalty or loss of benefits to 
which you are otherwise entitled. You may also withdraw from participation in this 
study at any time without any penalty or loss of benefits. If you decide you want to stop 
taking part in the study, it is recommended for your safety that you first talk to your 
doctor. If you withdraw from this study, you can still choose to be treated at MD 
Anderson. 
 
6. This study or your participation in it may be changed or stopped without your consent 
at any time by the study chair, IKENA Oncology, the U.S. Food and Drug 
Administration (FDA), the Office for Human Research Protections (OHRP), or the IRB 
of MD Anderson. 
 
7. You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study, including the results of all of your 
standard tests performed as part of this research, and you may be asked to sign 
another informed consent and authorization form stating your continued willingness to 
participate in this study. 
 
8. MD Anderson may benefit from your participation and/or what is learned in this study. 
 
9. This study is sponsored and/or supported by: IKENA Oncology. 
 
10. In a medical emergency, you may be cared for by someone who has a financial 
interest with the study sponsor(s)/supporter. If you have any questions about this, you 
may call the IRB at 713-792-6477. 
 
Future Research 
 
Data 
Your personal information is being collected as part of this study. These data may be 
used by researchers at MD Anderson and IKENA Oncology, and/or shared with other 
researchers and/or institutions for use in future research. 
 
Samples  
Samples (such as urine, blood and/or tissue) are being collected from you as part of 
this study. Researchers at MD Anderson may use any leftover samples that are stored 
at MD Anderson in future research. IKENA Oncology and Labcorp will not store 
leftover samples for future research. 
 


Protocol 2021-0077 
November 21, 2022 
Page 10 of 14 
 
If you do not want your samples or data to be used for future research, tell the study 
doctor. You may withdraw your samples at any time by telling your study team. If you 
decide to withdraw your samples, they will be returned to the lab they came from or 
destroyed. However, the data and test results already collected from your samples will 
be kept and may be used. 
 
Before being used or shared for future research, every effort will be made to remove 
your identifying information from any data and/or research samples. If all identifying 
information is removed, you will not be asked for additional permission before future 
research is performed. 
 
In some cases, all of your identifying information may not be removed before your data 
or research samples are used for future research. If future research is performed at 
MD Anderson, the researchers must get approval from the Institutional Review Board 
(IRB) of MD Anderson before your data and/or research samples can be used. At that 
time, the IRB will decide whether or not further permission from you is required. The 
IRB is a committee of doctors, researchers, and community members that is 
responsible for protecting study participants and making sure all research is safe and 
ethical. 
 
If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples 
 
Genetic Research 
Samples collected from you as part of this study may be used for genetic research, 
which may include whole genome sequencing. Whole genome sequencing is a type of 
testing in which researchers study your entire genetic makeup (DNA). This may help 
researchers learn how changes in the ordering of genes may affect a disease or 
response to treatment. If genetic research is done with your samples, those who have 
access to those samples may be able to identify you. The results of this research may 
also be able to be linked to you. 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information. This law 
generally will protect you in the following ways: 
• Health insurance companies and group health plans may not request your 
genetic information that we get from this research. 
• Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information 
that we get from this research when deciding to hire, promote, or fire you or 
when setting the terms of your employment. 
 
Be aware that this federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 


Protocol 2021-0077 
November 21, 2022 
Page 11 of 14 
 
Nor does this federal law prohibit discrimination based on an already known genetic 
disease or disorder. 
 
Outside Care 
 
Part of your care may be provided outside of MD Anderson by your home doctor(s). 
However, your first cycle (Cycle 1 Day 1) of treatment must be given at MD Anderson. 
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A. During the course of this study, MD Anderson will be collecting and using your PHI, 
including identifying information, information from your medical record, and study 
results. For legal, ethical, research, and safety-related reasons, your doctor and the 
research team may share your PHI with: 
• Federal agencies that require reporting of clinical study data (such as the FDA, 
National Cancer Institute [NCI], and OHRP) 
• The IRB and officials of MD Anderson 
• IKENA Oncology, who is a sponsor or supporter of this study, and/or any future 
sponsors/supporters of the study 
• Labcorp, a laboratory for the urine test for this study  
• Study monitors and auditors who verify the accuracy of the information 
• Individuals who put all the study information together in report form 
 
Study sponsors and/or supporters receive limited amounts of PHI. They may also view 
additional PHI in study records during the monitoring process. MD Anderson’s 
contracts require sponsors/supporters to protect this information and limit how they 
may use it.  
 
The results of this research may be published in scientific journals or presented at 
medical meetings, but your identity will not be disclosed. 
 
B. Signing this consent and authorization form is optional but you cannot take part in this 
study or receive study-related treatment if you do not agree and sign. 
 
C. MD Anderson will keep your PHI confidential when possible (according to state and 
federal law). However, in some situations, the FDA could be required to reveal the 
names of participants. 
 
Once disclosed outside of MD Anderson, federal privacy laws may no longer protect 
your PHI. 
 
D. The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed from 
the study and the data collected about you up to that point can be used and included 
in data analysis. However, no further information about you will be collected. If you 


Protocol 2021-0077 
November 21, 2022 
Page 12 of 14 
 
withdraw from the study, the study staff may ask if they can continue collecting the 
results of routine care from your medical record. 
 
E. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
 


Protocol 2021-0077 
November 21, 2022 
Page 13 of 14 
 
CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think about 
it, ask questions, and talk about it with others as needed. I give the study chair permission 
to enroll me on this study.  By signing this consent form, I am not giving up any of my 
legal rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
________________________________________ 
PRINTED NAME OF PARTICIPANT                 
 
LEGALLY AUTHORIZED REPRESENTATIVE (LAR) 
The following signature line should only be filled out when the participant does not have the 
capacity to legally consent to take part in the study and/or sign this document on his or her 
own behalf. 
 
_____________________________________________________ 
_________ 
SIGNATURE OF LAR 
DATE 
 
 
 
PRINTED NAME and RELATIONSHIP TO PARTICIPANT 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under Protocol 
2021-0077 
 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for vulnerable adult participants. If witnessing the assent  
of a pediatric participant, leave this line blank and sign on the witness to assent page instead. 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits and 
risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 
 
 


Protocol 2021-0077 
November 21, 2022 
Page 14 of 14 
 
TRANSLATOR 
I have translated the above informed consent as written (without additions or subtractions) 
into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
_____________________       _______________________________    
___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
 DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line below.) 
 
____________________________________________________   
___________ 
SIGNATURE OF WITNESS TO THE VERBAL TRANSLATION  
  
DATE  
(OTHER THAN TRANSLATOR, PARENT/GUARDIAN,  
OR STUDY CHAIR) 
 
_____________________________________________________ 
PRINTED NAME OF WITNESS TO THE VERBAL TRANSLATION