Breast Inflammatory Carcinoma, Recurrent Breast Inflammatory Carcinoma, Stage IV Breast Inflammatory Carcinoma
Conditions
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.
Interventions
DRUGEribulin Mesylate
Given IV
DRUGGrapiprant
Given PO
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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 * 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. * NOTE: HER2 positive status is defined as strongly positive (3+) staining score by immunohistochemistry (IHC), or gene amplification using fluorescence in situ hybridization (FISH), if performed. If IHC is equivocal (2+). HER2 negative status, which is determined by assays using IHC require negative (0 or 1+) staining score. If IHC is equivocal (2+) staining score * Has a measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (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 \>= 20 mm by chest X-ray, \>= 10 mm by computed tomography (CT) scan, \>= 10 mm 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 * 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/ultrasound (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 * Performance status (PS) of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) performance scale * Absolute neutrophil count (ANC) \>= 1,200 /mcL * Platelets \>= 100,000 /mcL * Hemoglobin (Hgb) \>= 9 g/dL * Total bilirubin =\< 1.5 x upper limit of normal (ULN) (up to =\< 3 x ULN for patients with liver metastasis) * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 2.5 x ULN (up to =\< 5 x ULN for patients with liver metastasis) * Cockcroft-Gault glomerular filtration rate (GFR) (mL/min/1.73 m\^2) \>= 50 * Left ventricular ejection fraction (LVEF) \>= 50% by echocardiogram (ECHO) or multigated acquisition (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 * 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 * WOCPB must have a negative urine pregnancy test no more than 7 days prior to starting treatment on-study * Male patients: A male patient must agree to use contraception during the treatment period and for at least 6 months after the last grapiuprant treatment and refrain from donating sperm during this period * Patient with human immunodeficiency virus (HIV) including current or prior infection would be included if: * With CD4+ T-cell (CD4+) counts \>= 350 cells/uL * Without a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections
Exclusion criteria
* Current chronic use of nonsteroidal anti-inflammatory drugs (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 * 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 * Has preexisting neuropathy \> grade 2 * Patients with a 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. * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Safety of Grapiprant and Eribulin Combination Treatment | Up to 21 days from the initial treatment | Dose-limiting toxicity was defined as probable, possible, and definite events that occurred in the first 21 days (Cycle 1), as prespecified in the protocol. |
| Determine the Efficacy of Grapiprant and Eribulin Combination Treatment | Up to 1 year | Clinical Benefit Rate (CBR) was defined as the ratio of patients who achieved a complete response (CR), partial response (PR), or stable disease (SD) (lasting \>24 weeks). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Duration of Response of the Proposed Treatment in Phase II | Up to 2 years | The time from observing the response to the grapiprant treatment until objective tumor progression (PD) |
| Determine the Time to First Response of the Proposed Treatment in Phase II | Up to 2 years | The time from starting grapiprant treatment until observing the response. |
| Determine Objective Response Rate (ORR) | Up to 1 year | The percentage of the patients who achieved complete response (CR) or partial response (PR). |
| Determine the Overall Survival (OS) of the Proposed Treatment | Up to 1.5 year | Overall survival (OS) was defined as the time from starting grapiprant treatment until death from any cause and was summarized using the Kaplan-Meier method, including the median with 95% confidence intervals. |
| Investigate the Predictive Biomarker for the Proposed Treatment | Baseline and Cycle 2 | Determine the association between treatment response and the change in prostaglandin E2 metabolite (PGEM) levels in urine samples collected pre- and post-treatment. |
| Determine Progression-free Survival (PFS) of the Proposed Treatment | Up to 1 year | Progression-free survival (PFS) was defined as the time from starting grapiprant treatment until objective tumor progression (PD) or death from any cause and was summarized using the Kaplan-Meier method, including the median with 95% confidence intervals. |
| Determine the Time to Progression (TTP) of the Proposed Treatment. | Up to 1 year | Time to progression (TTP), defined as the time from the start of grapiprant treatment to objective tumor progression (PD), was analyzed using the Kaplan-Meier method, and the median with 95% confidence intervals was reported. |
Countries
United States
Participant flow
Recruitment details
December 2021\ November 2022. All recruitment was done at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
8 patients were accrued and assessed for eligibility and 6 patients were assigned to the cohort.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib - Dose Level 0 Grapiprant 300 mg BID orally daily, and standard of care eribulin 1.4mg/m2 IV on Day 1 and 8. One cycle is defined as 21 days. | 6 |
| Phase Ib - Dose Level -1 Grapiprant 200 mg BID orally daily, and standard of care eribulin 1.4mg/m2 IV on Day 1 and 8. One cycle is defined as 21 days. | 0 |
| Phase II Recommended Grapiprant Dose (RP2D) from phase Ib and standard of care eribulin 1.4mg/m2 IV on Day 1 and 8. One cycle is defined as 21 days. | 0 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Diease Progression | 5 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase Ib - Dose Level 0 | Total |
|---|---|---|
| Age, Continuous | 43 years | 43 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants |
| Region of Enrollment United States | 6 participants | 6 participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 6 / 6 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 4 / 6 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Determine the Efficacy of Grapiprant and Eribulin Combination Treatment
Clinical Benefit Rate (CBR) was defined as the ratio of patients who achieved a complete response (CR), partial response (PR), or stable disease (SD) (lasting \>24 weeks).
Time frame: Up to 1 year
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine the Efficacy of Grapiprant and Eribulin Combination Treatment | 0 percentage of participants |
Primary
Determine the Safety of Grapiprant and Eribulin Combination Treatment
Dose-limiting toxicity was defined as probable, possible, and definite events that occurred in the first 21 days (Cycle 1), as prespecified in the protocol.
Time frame: Up to 21 days from the initial treatment
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine the Safety of Grapiprant and Eribulin Combination Treatment | 2 participants |
Secondary
Determine Objective Response Rate (ORR)
The percentage of the patients who achieved complete response (CR) or partial response (PR).
Time frame: Up to 1 year
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine Objective Response Rate (ORR) | 0 percentage of participants |
Secondary
Determine Progression-free Survival (PFS) of the Proposed Treatment
Progression-free survival (PFS) was defined as the time from starting grapiprant treatment until objective tumor progression (PD) or death from any cause and was summarized using the Kaplan-Meier method, including the median with 95% confidence intervals.
Time frame: Up to 1 year
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine Progression-free Survival (PFS) of the Proposed Treatment | 1.54 months |
Secondary
Determine the Duration of Response of the Proposed Treatment in Phase II
The time from observing the response to the grapiprant treatment until objective tumor progression (PD)
Time frame: Up to 2 years
Population: Participants treated at the RP2D in Phase II were intended to be evaluated. However, due to the study's termination during Phase Ib, no participants were analyzed for this objective.
Secondary
Determine the Overall Survival (OS) of the Proposed Treatment
Overall survival (OS) was defined as the time from starting grapiprant treatment until death from any cause and was summarized using the Kaplan-Meier method, including the median with 95% confidence intervals.
Time frame: Up to 1.5 year
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine the Overall Survival (OS) of the Proposed Treatment | 10.1 months |
Secondary
Determine the Time to First Response of the Proposed Treatment in Phase II
The time from starting grapiprant treatment until observing the response.
Time frame: Up to 2 years
Population: Participants treated at the RP2D in Phase II were intended to be evaluated. However, due to the study's termination during Phase Ib, no participants were analyzed for this objective.
Secondary
Determine the Time to Progression (TTP) of the Proposed Treatment.
Time to progression (TTP), defined as the time from the start of grapiprant treatment to objective tumor progression (PD), was analyzed using the Kaplan-Meier method, and the median with 95% confidence intervals was reported.
Time frame: Up to 1 year
Population: Termination was requested by study supporter IKENA oncology during Phase 1b.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib - Dose Level 0 | Determine the Time to Progression (TTP) of the Proposed Treatment. | 1.54 months |
Secondary
Investigate the Predictive Biomarker for the Proposed Treatment
Determine the association between treatment response and the change in prostaglandin E2 metabolite (PGEM) levels in urine samples collected pre- and post-treatment.
Time frame: Baseline and Cycle 2
Population: Patients with treatment response, compared with the non-responder group, were intended to be evaluated for changes in urine PGEM. However, due to the absence of treatment responders in this study, no patients were analyzed for this objective.