A Study of LY3127804 With Ramucirumab in Participants With Advanced Solid Tumors
- Conditions
- Solid Tumors
- Interventions
- Registration Number
- NCT02597036
- Lead Sponsor
- Eli Lilly and Company
- Brief Summary
The main purpose of this study is to evaluate the safety of the study drug known as LY3127804 given as monotherapy and in combination with Ramucirumab for participants with advanced or metastatic solid tumors. The study will also include a safety exploration for the combination of LY3127804 plus ramucirumab and paclitaxel
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 62
- Have a diagnosis of cancer that is advanced and/or metastatic.
- Have disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST ) version 1.1.
- Have adequate organ function.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Have discontinued previous treatments for cancer for at least 28 days or 5 half-lives prior to study enrolment.
- Have serious preexisting medical conditions.
- Have received treatment with a drug predominantly targeting Ang2 activity.
- Have symptomatic central nervous system (CNS) malignancy or metastasis.
- Have current hematologic malignancies.
- Have an active fungal, bacterial, and/or known viral infection.
- Have a corrected QT interval using Fridericia's correction (QTcF) of >470 msec on screening electrocardiogram (ECG) at several consecutive days of assessment.
- Have a known sensitivity to mAbs or other therapeutic proteins.
- Have a history of hypertensive crisis or hypertensive encephalopathy or current poorly controlled hypertension despite standard medical management.
- Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 3 months prior to receiving treatment.
- Receive anticoagulation therapy at therapeutic dose.
- Have experienced any arterial or venothrombotic or thromboembolic events within 6 months prior to study treatment.
- Have liver cirrhosis with a Child-Pugh class B or worse or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis.
- The participant is pregnant prior to randomization or breastfeeding.
- The participant has sensory peripheral neuropathy ≥ Grade 2 (Part E only).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part A LY3127804 LY3127804 Participants received escalating doses of 4 milligram per kilogram (mg/kg), 8 mg/kg, 12 mg/kg, 16 mg/kg, 20 mg/kg and 27 mg/kg LY3127804 administered as intravenous (IV) infusion on days 1 and 15 of a 28-day cycle. Part B LY3127804 + 8 mg/kg Ramucirumab Ramucirumab Participants received escalating doses of 8 mg/kg / 12 mg/kg / 16 mg/kg / 20 mg/kg / 27 mg/kg LY3127804 plus 8 mg/kg ramucirumab administered as IV infusion on days 1 and 15 of a 28-day cycle. Part E LY3127804 + Ramucirumab + Paclitaxel - Not Enrolled Paclitaxel Participants were to receive LY3127804 and Ramucirumab IV Q2W and Paclitaxel IV on day 1, 8, and 15 until participant qualifies for study discontinuation. Part D and E were not enrolled based on the primary and secondary outcomes/ results of Part A-C. Part B LY3127804 + 8 mg/kg Ramucirumab LY3127804 Participants received escalating doses of 8 mg/kg / 12 mg/kg / 16 mg/kg / 20 mg/kg / 27 mg/kg LY3127804 plus 8 mg/kg ramucirumab administered as IV infusion on days 1 and 15 of a 28-day cycle. Part C LY3127804 + 12 mg/kg Ramucirumab LY3127804 Participants received 20 mg/kg LY3127804 plus 12 mg/kg ramucirumab administered as IV infusion on days 1 and 15 of a 28-day cycle. Part C LY3127804 + 12 mg/kg Ramucirumab Ramucirumab Participants received 20 mg/kg LY3127804 plus 12 mg/kg ramucirumab administered as IV infusion on days 1 and 15 of a 28-day cycle. Part D LY3127804 + Ramucirumab - Not Enrolled Ramucirumab Participants were to receive LY3127804 and Ramucirumab IV Q2W until participant qualifies for study discontinuation. Part D and E were not enrolled based on the primary and secondary outcomes/ results of Part A-C. Part E LY3127804 + Ramucirumab + Paclitaxel - Not Enrolled LY3127804 Participants were to receive LY3127804 and Ramucirumab IV Q2W and Paclitaxel IV on day 1, 8, and 15 until participant qualifies for study discontinuation. Part D and E were not enrolled based on the primary and secondary outcomes/ results of Part A-C. Part D LY3127804 + Ramucirumab - Not Enrolled LY3127804 Participants were to receive LY3127804 and Ramucirumab IV Q2W until participant qualifies for study discontinuation. Part D and E were not enrolled based on the primary and secondary outcomes/ results of Part A-C. Part E LY3127804 + Ramucirumab + Paclitaxel - Not Enrolled Ramucirumab Participants were to receive LY3127804 and Ramucirumab IV Q2W and Paclitaxel IV on day 1, 8, and 15 until participant qualifies for study discontinuation. Part D and E were not enrolled based on the primary and secondary outcomes/ results of Part A-C.
- Primary Outcome Measures
Name Time Method Recommended Phase 2 Dose of LY3127804 Monotherapy and in Combination With Ramucirumab Baseline through Cycle 1 (28 Day Cycle) Recommended Phase 2 dose was determined based on observed safety, pharmacokinetics (PK) and efficacy. However maximum tolerated dose (MTD) was not determined. For the purpose of this study, the MTD is defined as the highest tested dose in a single-agent setting that has less than (\<) 33% probability of causing a DLT. MTD in the combination setting was determined based on the nature and timing of the DLTs in the combination setting. Dose-limiting toxicities were not reported in any treatment cohort. Therefore, the maximum tolerated LY3127804 dose could not be determined.
- Secondary Outcome Measures
Name Time Method Number of Participants With Anti-Ramucirumab Antibodies Cycle 1 Pre-Dose through 30 Days After Last Dose of Study Drug (Up to 5 Months) The number of participants who had treatment-emergent or follow-up emergent anti-drug antibodies (ADA) is reported. Participants with treatment-emergent ADA were defined as participants who had any sample from cycle 1 pre-Dose through 30 days after last dose of study drug that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Number of Participants With Dose Limiting Toxicities (DLTs) Baseline through Cycle 1 (28 Day Cycle) A dose limiting toxicity (DLT) defined as an adverse event (AE) during the first 21 days that was possibly related to the study drug and fulfilled any of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0: CTCAE Grade 3 nonhematologic toxicity, grade 4 neutropenia that lasted longer than 2 weeks, grade ≥3 thrombocytopenia complicated by hemorrhage, and any hematologic toxicity that caused a cycle delay of \>14 days; a DLT can be declared if a participant experiences increasing toxicity during treatment.
Pharmacokinetics: AUC of Ramucirumab in Combination With LY3127804 predose, end of infusion (1h), 24h, 96h, 168h, 336 h following Ramucirumab dose on day 1 Area under the serum concentration-time curve of ramucirumab in combination with LY3127804 over the dosing interval (AUC\[0-τ\]) from time 0 to 336 hours (τ) was evaluated following the first dose.
Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC) of LY3127804 predose, end of infusion (1h), 2h, 24h, 96h, 168h, 336 h following dose on day 1 and at predose, end of infusion (1h), 24h, 168h and 336 h following dose on day 15 and at predose, end of infusion (1h), 2h, 168h, 336h following dose on day 29 Area under the plasma concentration-time curve of LY3127804 over the dosing interval (AUC\[0-τ\]) from time 0 to 336 hours (h) was evaluated.
Number of Participants With Anti-LY3127804 Antibodies Cycle 1 Pre-Dose through 30 Days After Last Dose of Study Drug (Up To 5 Months) The number of participants who had treatment-emergent or follow-up emergent anti-drug antibodies (ADA) is reported. Participants with treatment-emergent ADA were defined as participants who had any sample from cycle 1 pre-Dose through 30 days after last dose of study drug that was a 4-fold increase (2 dilution increase) in immunogenicity titer over the baseline titer, or participants who tested negative at baseline and positive post-baseline (at titer of ≥1:20).
Percentage of Participants Who Exhibit Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] Baseline through Measured Progressive Disease or Death (Up to 4 Months) ORR defined as the percentage of participants who achieve a CR or PR as assessed by RECIST v.1.1. The ORR is the number of participants with a complete response (CR) or partial response (PR) divided by the number of randomized participants recorded between the date of randomization and the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever comes first. Complete response (CR) is defined as disappearance of all target (and non-target) lesions, and normalization of tumor marker level. Partial response (PR) is defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum of longest diameters.
Progression Free Survival (PFS) Baseline to Measured Progressive Disease or Death (Up to 4 Months) Progression-free survival (PFS) time is defined as the time from the date of randomization to the first date of documented objective progressive disease (PD) or death from any cause. For participants who were not known to have had objective PD as of the data inclusion cut-off date for a particular analysis, PFS was censored at the date of the last objective progression-free disease assessments. For participants who took any subsequent systemic anticancer therapy prior to progression, PFS was censored at the date of the last objective progression-free disease assessment prior to the start date of any subsequent systemic anticancer therapy.
Trial Locations
- Locations (3)
SMO Sarah Cannon Research Inst.
🇺🇸Nashville, Tennessee, United States
Tennessee Oncology PLLC
🇺🇸Nashville, Tennessee, United States
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
🇪🇸Barcelona, Spain
SMO Sarah Cannon Research Inst.🇺🇸Nashville, Tennessee, United States