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

• ClinicalTrials.gov Identifier: NCT01234402
• Recruitment Status: Completed
• First Posted: November 4, 2010
• Results First Posted: August 14, 2019
• Last Update Posted: August 14, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: November 3, 2010
• First Posted Date: November 4, 2010
• Results First Submitted Date: June 13, 2019
• Results First Posted Date: August 14, 2019
• Last Update Posted Date: August 14, 2019
• Study Start Date: March 2011
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 21, 2019)

Progression-Free Survival (PFS) [ Time Frame: From Date of Randomization until Disease Progression or Death Due to Any Cause (Up To 97 weeks) ]

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.

• Original Primary Outcome Measures (submitted: November 3, 2010): Progression-Free Survival (PFS) [ Time Frame: Approximately 22 Months ]

Current Secondary Outcome Measures (submitted: July 21, 2019)

• Overall Survival (OS) [ Time Frame: From Date of Randomization until Death Due to Any Cause (Up To 160 weeks) ]
  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.
• Percentage of Participants With Objective Response Rate (ORR) [ Time Frame: From Date of Randomization until Disease Progression/Recurrence (Up to 97 weeks) ]
  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.
• Duration of Response [ Time Frame: From Date of CR, PR until Disease Progression or Death Due to Any Cause (Up To 97 weeks) ]
  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.
• Number of Participants With Adverse Events (AEs) [ Time Frame: Up To 160 Weeks ]
  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.
• Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up To 160 Weeks ]
  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.
• Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or Icrucumab [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
• Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab [ Time Frame: Cycle 2,4,6,8,0,12,14,16,18,22: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
  Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or Icrucumab.
• Area Under the Concentration Versus Time Curve From Time Zero to Infinity of Ramucirumab or Icrucumab [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
  Area Under the Concentration (AUC) Versus Time Curve From Time Zero to Infinity of Ramucirumab and Icrucumab.
• Terminal Half-life (t½) of Ramucirumab or Icrucumab [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
  Terminal half-life (t½) of Ramucirumab and Icrucumab.
• Clearance (Cl) of Ramucirumab or Icrucumab [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
  Clearance (Cl) of Ramucirumab and Icrucumab.
• Volume of Distribution at Steady State (Vss) of Ramucirumab or Icrucumab [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]
  Volume of Distribution at Steady State (Vss) of Ramucirumab and Icrucumab.
• Number of Participants With Anti-Ramucirumab and Anti-Icrucumab Antibodies [ Time Frame: Cycle 1: Pre-infusion, 1h, 48h, 72h, 168, 336h post infusion ]

Original Secondary Outcome Measures (submitted: November 3, 2010)

• Overall Survival (OS) [ Time Frame: Approximately 22 Months ]
• Objective Response Rate (ORR) [ Time Frame: Approximately 22 Months ]
• Duration of Response [ Time Frame: Approximately 22 Months ]
• Number of Participants with Adverse Events (AEs) [ Time Frame: Approximately 22 Months ]
• Number of Participants with Serious Adverse Events (SAEs) [ Time Frame: Approximately 22 Months ]
• Maximum Concentration (Cmax) Ramucirumab Drug Product (DP) or IMC-18F1 [ Time Frame: Approximately 22 Months ]
  Prior to and 1.5 hours after the infusion in Cycles 1, 2, 3, 4, 6, and every 2 Cycles thereafter
• Minimum Concentration (Cmin) Ramucirumab Drug Product (DP) or IMC-18F1 [ Time Frame: Approximately 22 Months ]
  Prior to and 1.5 hours after the infusion in Cycles 1, 2, 3, 4, 6, and every 2 Cycles thereafter
• Serum Antibody Assessment of Anti-Ramucirumab and Anti-IMC-18F1 [ Time Frame: Approximately 22 Months ]
  Prior to infusion in Cycles 1, 2, 3, 6, and every 2 Cycles thereafter

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Biological: Ramucirumab DP

  10 mg/kg I.V.

  Day 1 of every-21-day cycle

  Other Names:

  • IMC-1121B
  • LY3009806
• Biological: IMC-18F1

  12 mg/kg I.V.

  Days 1 and 8 of every-21-day cycle

  Other Names:

  • Icrucumab
  • LY3012212
• Drug: Capecitabine

  1000 mg/m^2 orally

  Twice a day for 14 days

Study Arms

• Experimental: Ramucirumab DP + Capecitabine
  Cycles repeat until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant.
  Interventions:

  • Biological: Ramucirumab DP
  • Drug: Capecitabine
• Experimental: Icrucumab + Capecitabine
  Cycles repeat until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the participant.
  Interventions:

  • Biological: IMC-18F1
  • Drug: Capecitabine
• Active Comparator: Capecitabine*

  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.

  Intervention: Drug: Capecitabine

• Publications *: Vahdat LT, Layman R, Yardley DA, Gradishar W, Salkeni MA, Joy AA, Garcia AA, Ward P, Khatcheressian J, Sparano J, Rodriguez G, Tang S, Gao L, Dalal RP, Kauh J, Miller K. Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer. Oncologist. 2017 Mar;22(3):245-254. doi: 10.1634/theoncologist.2016-0265. Epub 2017 Feb 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 11, 2013): 153
• Original Estimated Enrollment (submitted: November 3, 2010): 150
• Actual Study Completion Date: July 2017
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01234402
• Other Study ID Numbers: 13944; CP20-0903 ( Other Identifier: ImClone LLC ); I4Y-IE-JCDD ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Lilly provides access to the individual patient data from studies on approved medicines and indications as defined by the sponsor specific information on ClinicalStudyDataRequest.com.

This access is provided in a timely fashion after the primary publication is accepted. Researchers need to have an approved research proposal submitted through ClinicalStudyDataRequest.com. Access to the data will be provided in a secure data sharing environment after signing a data sharing agreement.

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Chief Medical Officer, ImClone LLC
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: July 2019