Trial Outcomes & Findings for A Study of Ramucirumab (LY3009806) in Children With Refractory Solid Tumors (NCT NCT02564198)

Last Updated: 2021-08-17

Results Overview

A DLT is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria, graded according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0: 1\. Any death not clearly due to the underlying disease or extraneous causes 2. Neutropenic fever 2. Any Grade ≥3 non-hematologic toxicity 3. Grade ≥4 neutropenia or thrombocytopenia \>7 days 4. Grade ≥3 thrombocytopenia with bleeding 5. Grade ≥3 nausea/vomiting or diarrhea\>72 hours with adequate antiemetic and other supportive care 6. Grade ≥3 fatigue ≥1 week 7. Grade ≥3 electrolyte abnormality that lasts\>72 hours, unless the Participant has clinical symptoms, in which case all Grade 3+electrolyte abnormality regardless of duration should count as a DLT. 8\. Grade ≥3 prolongation of QT interval corrected using the Fridericia formula on 2 separate electrocardiogram readings approximately 5 min apart.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

29 participants

Primary outcome timeframe

Baseline to Study Completion (Up to 42 Months)

Results posted on

2021-08-17

Participant Flow

Completers included participants who had progressive disease, death due to any cause or alive and on study at conclusion, but off treatment.

Participant milestones

Participant milestones
Measure	8 mg/kg Ramucirumab (Part A) Participants received 8 milligram per kilogram \[mg/kg\] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Overall Study STARTED	8	15	6
Overall Study Received at Least 1 Dose of Study Drug	8	15	6
Overall Study COMPLETED	6	10	6
Overall Study NOT COMPLETED	2	5	0

Reasons for withdrawal

Reasons for withdrawal
Measure	8 mg/kg Ramucirumab (Part A) Participants received 8 milligram per kilogram \[mg/kg\] Ramucirumab administered as an intravenous infusion every 2 weeks (Q2W) with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Overall Study Withdrawal by Subject	2	4	0
Overall Study Adverse Event	0	1	0

Baseline Characteristics

A Study of Ramucirumab (LY3009806) in Children With Refractory Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	Total n=29 Participants Total of all reporting groups
Age, Continuous	15.8 years STANDARD_DEVIATION 3.33 • n=5 Participants	11.9 years STANDARD_DEVIATION 5.59 • n=7 Participants	9.7 years STANDARD_DEVIATION 5.9 • n=5 Participants	12.5 years STANDARD_DEVIATION 5.4 • n=4 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	12 Participants n=4 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	9 Participants n=7 Participants	4 Participants n=5 Participants	17 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	6 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	12 Participants n=7 Participants	4 Participants n=5 Participants	22 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	12 Participants n=7 Participants	4 Participants n=5 Participants	23 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Region of Enrollment United States	8 Participants n=5 Participants	15 Participants n=7 Participants	6 Participants n=5 Participants	29 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to Study Completion (Up to 42 Months)

Population: All randomized participants from Part A, who received at least one dose of study drug.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Part A: Number of Participants With Dose Limiting Toxicities (DLTs): Maximum Tolerated Dose of Ramucirumab	1 Participants	1 Participants	—

PRIMARY outcome

Timeframe: Predose, Cycle 1 Day 1 (end of infusion (EOI), 1 hour after EOI) and Cycle 1 Day 43 (1 hour after EOI)

Population: All randomized participants who received at least one dose of study drug and had evaluable PK data. Per protocol, 12 mg/kg Ramucirumab PK data were reported per dose level combining Part A and B participants.

Population Pharmacokinetics (PK): Minimum observed plasma concentration of Ramucirumab.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=19 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 1 Day 1	30.0 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 32	48.3 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 41	—
Population Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 1 Day 43	53.6 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 31	80.2 microgram per milliliter (µg/mL) Geometric Coefficient of Variation 44	—

PRIMARY outcome

Timeframe: Predose Cycle 1 Day 1 through Follow-Up (Up to 42 Months)

Population: All randomized participants who received at least one dose of study drug.

Number of participants with positive treatment emergent anti-ramucirumab antibodies was summarized by treatment group. A treatment-emergent anti-drug antibodies (TEADA) sample was defined as: a post treatment sample with at least a 4-fold increase in titer from pre treatment sample; or 1:20 post treatment titer for participants that had no detectable ADA titer at baseline.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Number of Participants With Anti-Ramucirumab Antibodies	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline to Date of Objective Disease Progression (Up to 42 Months)

Population: All randomized participants who received at least one dose of study drug.

Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants per cohort with at least 1 measurable lesion, multiplied by 100. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Overall Response Rate (ORR): Percentage of Participants Who Achieve Complete Response (CR) or Partial Response (PR)	0 Percentage of participants Interval 0.0 to 41.0	0 Percentage of participants Interval 0.0 to 23.2	0 Percentage of participants Interval 0.0 to 45.9

SECONDARY outcome

Timeframe: Baseline to Date of Objective Disease Progression (Up to 42 Months)

Population: All randomized participants who received at least one dose of study drug.

Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Percentage of Participants With a Best Overall Response of Complete Response (CR), Partial Response (PR) or Stable Disease (SD): Disease Control Rate (DCR)	62.5 Percentage of participants Interval 29.0 to 96.3	40.0 Percentage of participants Interval 17.7 to 71.1	33.3 Percentage of participants Interval 4.3 to 77.7

SECONDARY outcome

Timeframe: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up to 42 Months)

Population: Zero participants analyzed. Duration of response was not evaluable, as there were no participants with CR or PR.

DOR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. PD was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to Date of Death from Any Cause (Up to 42 Months)

Population: All randomized participants who received at least one dose of study drug.

Overall survival is defined as the time from date of randomization to the date of death (due to any cause). For participants whose last known status is alive at the data cutoff date for the analysis, time will be censored as the last contact date prior to the data cutoff date.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab (Part A) n=8 Participants Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 Participants Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Overall Survival	NA Months There were not enough events/deaths to compute a median or 95% confidence interval.	NA Months There were not enough events/deaths to compute a median or 95% confidence interval.	NA Months There were not enough events/deaths to compute a median or 95% confidence interval.

Adverse Events

8 mg/kg Ramucirumab (Part A)

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

12 mg/kg Ramucirumab (Part A)

Serious events: 7 serious events

Other events: 15 other events

Deaths: 0 deaths

12 mg/kg Ramucirumab (Part B)

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	8 mg/kg Ramucirumab (Part A) n=8 participants at risk Participants received 8 mg/kg Ramucirumab administered as an intravenous infusion Q2W with 3 doses per 42 day cycle.	12 mg/kg Ramucirumab (Part A) n=15 participants at risk Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.	12 mg/kg Ramucirumab (Part B) n=6 participants at risk Participants received 12 mg/kg Ramucirumab as an intravenous injection Q2W with 3 doses per cycle.
Gastrointestinal disorders Abdominal pain	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
General disorders Pyrexia	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	20.0% 3/15 • Number of events 3 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Infections and infestations Infection	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Infections and infestations Kidney infection	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	16.7% 1/6 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fracture	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Nervous system disorders Headache	12.5% 1/8 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	16.7% 1/6 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Nervous system disorders Paraesthesia	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Nervous system disorders Peripheral motor neuropathy	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Nervous system disorders Seizure	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	16.7% 1/6 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Renal and urinary disorders Urinary tract obstruction	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	13.3% 2/15 • Number of events 2 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	13.3% 2/15 • Number of events 2 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.00% 0/8 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	6.7% 1/15 • Number of events 2 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Vascular disorders Hypertension	12.5% 1/8 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.
Vascular disorders Hypotension	12.5% 1/8 • Number of events 1 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/15 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.	0.00% 0/6 • Baseline, up to 4 years 8 months All randomized participants who received at least one dose of study drug.