Study of Icrucumab (IMC-18F1) or Ramucirumab Drug Product (DP) in Combination With Capecitabine or Capecitabine on Previously Treated Breast Cancer Patients

Study Overview
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Brief Summary
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An open-label, multicenter, randomized, Phase 2 trial in which participant with unresectable, locally advanced or metastatic breast cancer who have been previously treated with anthracycline and taxane therapy receive ramucirumab DP or Icrucumab (IMC-18F1) administered on an every-21-day cycle (in combination with oral capecitabine therapy; capecitabine is administered twice a day on Days 1-14 of each cycle). Approximately 150 participants will be randomized in a 1:1:1 ratio to either ramucirumab DP or Icrucumab (IMC-18F1) in combination with capecitabine (Arm A and Arm B, respectively) or capecitabine monotherapy (Arm C). Randomization will be stratified by triple-negative receptor status (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor-2 [HER2/neu]-negative) (yes/no) and receipt of prior antiangiogenic therapy. Treatment with the study medication(s) will continue until disease progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the participant, or investigator decision. Capecitabine dose reductions in the setting of significant myelosuppression, hand-and-foot syndrome, or diarrhea will be required.

Official Title
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An Open-Label, Multicenter, Randomized Phase 2 Study Evaluating the Safety and Efficacy of Ramucirumab (IMC-1121B) Drug Product or Icrucumab (IMC-18F1) in Combination With Capecitabine or Capecitabine Monotherapy, in Unresectable, Locally Advanced or Metastatic Breast Cancer Patients Previously Treated With Anthracycline and Taxane Therapy

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: Ramucirumab DP
* Biological: IMC-18F1
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has histologically or cytologically confirmed breast cancer which at the time of study entry is either Stage III disease not amenable to curative therapy or Stage IV disease Has measurable or nonmeasurable disease Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Has received prior anthracycline therapy Has received prior taxane therapy Participants with human epidermal growth factor receptor-2 (HER2) positive disease must have progressed on or following trastuzumab Participants with hormone receptor-positive disease must have progressed on or following hormone therapy Has received ≤ 3 prior chemotherapy regimens in any setting (a regimen is defined as any agent[s] that has been administered for more than 1 cycle; sequential neoadjuvant/adjuvant treatment is considered 1 regimen) Has completed any prior radiotherapy ≥ 4 weeks prior to randomization Has completed any prior hormonal therapy ≥ 2 weeks prior to randomization Has adverse events (AEs) that have resolved to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v 4.0) from all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy,or hormonal therapy Has adequate hematologic, coagulation, hepatic and renal function Does not have: cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis Has urinary protein is ≤ 1+ on dipstick or routine urinalysis; if urine protein ≥ 2+, a 24-hour urine collection must demonstrate < 1000 mg of protein in 24 hours to allow participation in the study Agrees to use adequate contraception during the study period and for 12 weeks after the last dose of study medication Exclusion Criteria: Has a concurrent active malignancy other than adequately treated nonmelanomatous skin cancer, curatively treated cervical carcinoma in situ, or other noninvasive carcinoma or in situ neoplasm. A participant with previous history of malignancy is eligible, provided that there has been a disease-free interval for > 3 years Has a known sensitivity to capecitabine, any of its components, or other drugs formulated with polysorbate 80 Has a known sensitivity to 5-fluorouracil (5-FU) Has a known dihydropyrimidine dehydrogenase deficiency Has received prior capecitabine treatment for advanced breast cancer Has received investigational therapy within 2 weeks prior to randomization Has received bevacizumab within 4 weeks prior to randomization Has received more than 1 prior antiangiogenic agent for breast cancer Has a known sensitivity to agents of similar biologic composition as ramucirumab DP or Icrucumab (IMC-18F1), or other agents that specifically target vascular endothelial growth factor (VEGF) Has an acute/subacute bowel obstruction or history of chronic diarrhea requiring ongoing medical intervention Has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders Has experienced a Grade ≥ 3 bleeding event within 3 months prior to randomization Is receiving prophylactic or therapeutic anticoagulation with warfarin or any other oral anticoagulant Has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, symptomatic anemia, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorder in the opinion of the investigator Has experienced any arterial thrombotic or thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident within 6 months prior to randomization Has brain metastases, uncontrolled spinal cord compression, or leptomeningeal disease Has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy Has received a prior allogeneic organ or tissue transplantation Has undergone major surgery within 4 weeks prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization Has had a serious nonhealing wound, ulcer, or bone fracture within 4 weeks prior to randomization Has known HIV or AIDS infection Has an elective or planned major surgery to be performed during the course of the trial Participant is pregnant or lactating

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab DP + Capecitabine<br>Cycles repeat until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant. | Biological: Ramucirumab DP<br>* 10 mg/kg I.V. Day 1 of every-21-day cycle<br>* Other names: LY3009806;Drug: Capecitabine<br>* 1000 mg/m^2 orally Twice a day for 14 days<br>|
| Experimental: Icrucumab + Capecitabine<br>Cycles repeat until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant. | Biological: IMC-18F1<br>* 12 mg/kg I.V. Days 1 and 8 of every-21-day cycle<br>* Other names: LY3012212;Drug: Capecitabine<br>* 1000 mg/m^2 orally Twice a day for 14 days<br>|
| Active Comparator: Capecitabine*<br>Crossover Study: * At the discretion of the investigator, participants will be eligible to receive either ramucirumab DP or Icrucumab (IMC-18F1) in combination with capecitabine, after radiographic disease progression while on capecitabine. The investigator will decide which investigational product will be given. Cycles repeat every 21 days until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant. | Drug: Capecitabine<br>* 1000 mg/m^2 orally Twice a day for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from the date of randomization until the date of objectively determined progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) or death from any cause, whichever is first. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 millimeter (mm) and the appearance of ≥1 new lesions was progression. Participants who did not progress, were lost to follow-up, or had missed 2 or more scheduled tumor assessments were censored at the day of their last adequate tumor assessment. | From Date of Randomization until Disease Progression or Death Due to Any Cause (Up To 97 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive. | From Date of Randomization until Death Due to Any Cause (Up To 160 weeks) | 
| Percentage of Participants With Objective Response Rate (ORR) | The ORR is the number of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1 from the start of the treatment until disease progression/recurrence. CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter. Disease progression is defined as ≥20% increase in the sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that was the smallest on study); sum must have demonstrated an absolute increase of ≥5 mm and the appearance of ≥1 new lesions was progression. | From Date of Randomization until Disease Progression/Recurrence (Up to 97 weeks) | 
| Duration of Response | Duration of response is measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the criteria for progressive disease (PD) is met (taking as a reference for PD that smallest measurement recorded since the treatment started), or death, is objectively documented.CR was defined as the disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to <10 mm. PR was defined as ≥30% decrease in the sum of the diameters of target lesions (including the short axes of any target lymph nodes), taking as reference the baseline sum diameter.PD defined as ≥20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Sum must also have demonstrated an absolute increase of ≥5 mm, or the appearance of 1 or more new lesions was considered progression. | From Date of CR, PR until Disease Progression or Death Due to Any Cause (Up To 97 weeks) | 
| Number of Participants With Adverse Events (AEs) | Adverse event (AE) will be regarded as treatment-emergent if onset date occurs any time on or after the administration of the first dose of study treatment up to 30 days after the last dose of study treatment (or up to any time if related to study treatment); or it occurs prior to first dose date and worsens while on therapy or up to 30 days after the last dose of study treatment (or up to any time if related to study treatment). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Up To 160 Weeks | 
| Number of Participants With Serious Adverse Events (SAEs) | SAE was defined as any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or caused prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect; Required intervention to prevent permanent impairment/damage; Was an important medical event (defined as a medical event that may not have been immediately life-threatening or resulted in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the participant or may require intervention to prevent one of the other serious outcomes listed in the definition above). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Up To 160 Weeks | 
| Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or Icrucumab |  | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab | Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab. | Cycle 2,4,6,8,0,12,14,16,18,22: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Area Under the Concentration Versus Time Curve From Time Zero to Infinity of Ramucirumab or Icrucumab | Area Under the Concentration (AUC) Versus Time Curve From Time Zero to Infinity of Ramucirumab and Icrucumab. | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Terminal Half-life (t½) of Ramucirumab or Icrucumab | Terminal half-life (t½) of Ramucirumab and Icrucumab. | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Clearance (Cl) of Ramucirumab or Icrucumab | Clearance (Cl) of Ramucirumab and Icrucumab. | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Volume of Distribution at Steady State (Vss) of Ramucirumab or Icrucumab | Volume of Distribution at Steady State (Vss) of Ramucirumab and Icrucumab. | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 
| Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies |  | Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer