Trial Outcomes & Findings for A Study of Ramucirumab (LY3009806) or Merestinib (LY2801653) in Advanced or Metastatic Biliary Tract Cancer (NCT NCT02711553)

Last Updated: 2025-08-03

Results Overview

PFS time was measured from the date of randomization until the first radiographic documentation of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. 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. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

309 participants

Primary outcome timeframe

Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)

Results posted on

2025-08-03

Participant Flow

In the Participant Flow, participants who completed were those who died due to any cause or were alive and on study at conclusion but off treatment.

Participant milestones

Participant milestones
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Overall Study STARTED	106	52	102	49
Overall Study Received at Least 1 Dose of Study Drug	104	52	102	48
Overall Study COMPLETED	100	47	92	45
Overall Study NOT COMPLETED	6	5	10	4

Reasons for withdrawal

Reasons for withdrawal
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 8 mg/kg ramucirumab plus 25 mg/square meter (mg/m²) cisplatin and 1000 mg/m² gemcitabine intravenously (IV) on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Overall Study Withdrawal by Subject	2	1	1	0
Overall Study Lost to Follow-up	3	3	6	3
Overall Study On Study Treatment at Study Conclusion	1	1	3	1

Baseline Characteristics

All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=106 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=52 Participants Participants received placebo (indistinguishable and equivalent volume to ramucirumab) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=102 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=49 Participants Participants received placebo (indistinguishable to merestinib) orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days. Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).	Total n=309 Participants Total of all reporting groups
Region of Enrollment Argentina	11 Participants n=106 Participants	3 Participants n=52 Participants	8 Participants n=102 Participants	3 Participants n=49 Participants	25 Participants n=309 Participants
Age, Continuous	63.49 years STANDARD_DEVIATION 9.76 • n=106 Participants	57.06 years STANDARD_DEVIATION 11.67 • n=52 Participants	60.95 years STANDARD_DEVIATION 9.14 • n=102 Participants	62.00 years STANDARD_DEVIATION 9.14 • n=49 Participants	61.33 years STANDARD_DEVIATION 10.01 • n=309 Participants
Sex: Female, Male All randomized participants · Female	60 Participants n=106 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	26 Participants n=52 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	54 Participants n=102 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	22 Participants n=49 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	162 Participants n=309 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.
Sex: Female, Male All randomized participants · Male	46 Participants n=106 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	26 Participants n=52 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	48 Participants n=102 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	27 Participants n=49 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	147 Participants n=309 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.
Sex: Female, Male All randomized participants who received at least 1 dose of study drug · Female	59 Participants n=104 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	26 Participants n=52 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	54 Participants n=102 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	21 Participants n=48 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	160 Participants n=306 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.
Sex: Female, Male All randomized participants who received at least 1 dose of study drug · Male	45 Participants n=104 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	26 Participants n=52 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	48 Participants n=102 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	27 Participants n=48 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.	146 Participants n=306 Participants • All randomized participants and all randomized participants who received at least 1 dose of study drug to align gender specific adverse event numbers.
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=106 Participants	0 Participants n=52 Participants	0 Participants n=102 Participants	0 Participants n=49 Participants	0 Participants n=309 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=106 Participants	0 Participants n=52 Participants	0 Participants n=102 Participants	0 Participants n=49 Participants	0 Participants n=309 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	106 Participants n=106 Participants	52 Participants n=52 Participants	102 Participants n=102 Participants	49 Participants n=49 Participants	309 Participants n=309 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=106 Participants	0 Participants n=52 Participants	1 Participants n=102 Participants	0 Participants n=49 Participants	1 Participants n=309 Participants
Race (NIH/OMB) Asian	20 Participants n=106 Participants	11 Participants n=52 Participants	26 Participants n=102 Participants	9 Participants n=49 Participants	66 Participants n=309 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=106 Participants	0 Participants n=52 Participants	0 Participants n=102 Participants	0 Participants n=49 Participants	0 Participants n=309 Participants
Race (NIH/OMB) Black or African American	1 Participants n=106 Participants	1 Participants n=52 Participants	1 Participants n=102 Participants	1 Participants n=49 Participants	4 Participants n=309 Participants
Race (NIH/OMB) White	78 Participants n=106 Participants	35 Participants n=52 Participants	70 Participants n=102 Participants	38 Participants n=49 Participants	221 Participants n=309 Participants
Race (NIH/OMB) More than one race	0 Participants n=106 Participants	0 Participants n=52 Participants	0 Participants n=102 Participants	0 Participants n=49 Participants	0 Participants n=309 Participants
Race (NIH/OMB) Unknown or Not Reported	7 Participants n=106 Participants	5 Participants n=52 Participants	4 Participants n=102 Participants	1 Participants n=49 Participants	17 Participants n=309 Participants
Region of Enrollment Hungary	5 Participants n=106 Participants	7 Participants n=52 Participants	4 Participants n=102 Participants	1 Participants n=49 Participants	17 Participants n=309 Participants
Region of Enrollment United States	12 Participants n=106 Participants	3 Participants n=52 Participants	6 Participants n=102 Participants	4 Participants n=49 Participants	25 Participants n=309 Participants
Region of Enrollment Czechia	2 Participants n=106 Participants	2 Participants n=52 Participants	5 Participants n=102 Participants	2 Participants n=49 Participants	11 Participants n=309 Participants
Region of Enrollment United Kingdom	4 Participants n=106 Participants	2 Participants n=52 Participants	5 Participants n=102 Participants	3 Participants n=49 Participants	14 Participants n=309 Participants
Region of Enrollment Russia	9 Participants n=106 Participants	2 Participants n=52 Participants	4 Participants n=102 Participants	6 Participants n=49 Participants	21 Participants n=309 Participants
Region of Enrollment Spain	8 Participants n=106 Participants	3 Participants n=52 Participants	10 Participants n=102 Participants	1 Participants n=49 Participants	22 Participants n=309 Participants
Region of Enrollment Austria	3 Participants n=106 Participants	2 Participants n=52 Participants	1 Participants n=102 Participants	0 Participants n=49 Participants	6 Participants n=309 Participants
Region of Enrollment South Korea	8 Participants n=106 Participants	6 Participants n=52 Participants	12 Participants n=102 Participants	4 Participants n=49 Participants	30 Participants n=309 Participants
Region of Enrollment Sweden	1 Participants n=106 Participants	0 Participants n=52 Participants	3 Participants n=102 Participants	2 Participants n=49 Participants	6 Participants n=309 Participants
Region of Enrollment Turkey	6 Participants n=106 Participants	7 Participants n=52 Participants	7 Participants n=102 Participants	3 Participants n=49 Participants	23 Participants n=309 Participants
Region of Enrollment Belgium	6 Participants n=106 Participants	1 Participants n=52 Participants	3 Participants n=102 Participants	4 Participants n=49 Participants	14 Participants n=309 Participants
Region of Enrollment Taiwan	9 Participants n=106 Participants	5 Participants n=52 Participants	13 Participants n=102 Participants	4 Participants n=49 Participants	31 Participants n=309 Participants
Region of Enrollment Denmark	1 Participants n=106 Participants	1 Participants n=52 Participants	3 Participants n=102 Participants	1 Participants n=49 Participants	6 Participants n=309 Participants
Region of Enrollment Mexico	4 Participants n=106 Participants	0 Participants n=52 Participants	3 Participants n=102 Participants	0 Participants n=49 Participants	7 Participants n=309 Participants
Region of Enrollment Australia	6 Participants n=106 Participants	2 Participants n=52 Participants	2 Participants n=102 Participants	4 Participants n=49 Participants	14 Participants n=309 Participants
Region of Enrollment France	8 Participants n=106 Participants	5 Participants n=52 Participants	5 Participants n=102 Participants	2 Participants n=49 Participants	20 Participants n=309 Participants
Region of Enrollment Germany	3 Participants n=106 Participants	1 Participants n=52 Participants	8 Participants n=102 Participants	5 Participants n=49 Participants	17 Participants n=309 Participants

PRIMARY outcome

Timeframe: Randomization to Progressive Disease or Death from Any Cause (Up To 20 Months)

Population: All randomized participants. Censored participants: 8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 29; 80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine = 34; Pooled Placebo = 25. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=106 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=102 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=101 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Progression Free Survival (PFS)	6.47 Months Interval 3.68 to 8.51	6.97 Months Interval 4.34 to 9.79	6.64 Months Interval 4.11 to 9.72

SECONDARY outcome

Timeframe: Randomization to Date of Death from Any Cause (Up To 48 Months)

OS defined as the time from from randomization to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=106 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=102 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=101 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Overall Survival (OS)	10.45 Months Interval 8.48 to 11.76	14.03 Months Interval 11.96 to 16.36	13.04 Months Interval 11.4 to 15.31

SECONDARY outcome

Timeframe: Randomization to Disease Progression (Up To 30 Months)

Population: All randomized participants. Pooling is done in the placebo arm (Pooled Placebo) from both arms (Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine and Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine) for analysis purpose and combined as pre-specified in protocol.

ORR was the number of participants who achieve a best overall response of CR or PR divided by the total number of participants randomized to the corresponding treatment arm as per Response Evaluation Criteria in Solid Tumors (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 longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. PD is defined as 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 + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=106 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=102 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=101 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)	31.1 Percentage of participants Interval 22.3 to 39.9	19.6 Percentage of participants Interval 11.9 to 27.3	32.7 Percentage of participants Interval 23.5 to 41.8

SECONDARY outcome

Timeframe: Randomization to Disease Progression (Up To 30 Months)

Disease Control Rate (DCR) was the number of participants who achieve a best overall response of CR, PR, or SD divided by the total number of participants randomized to the corresponding treatment arm as per 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. 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 is defined as 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 + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=106 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=102 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=101 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)	81.1 Percentage of participants Interval 73.7 to 88.6	83.3 Percentage of participants Interval 76.1 to 90.6	78.2 Percentage of participants Interval 70.2 to 86.3

SECONDARY outcome

Timeframe: C1 D8, C2 D1, C3 D1, C4 D1,C5 D1,C7 D1, C9 D1 and C13 D1: Within 3 days Prior to Infusion(PTI)

Population: All participants who received at least one dose of study drug and had evaluable PK data. As per protocol, Cmin of merestinib was not measured.

PK was determined by the minimum observed plasma concentration (Cmin). 1 Cycle (C) = 21 days (D).

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=86 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 1 Day 8 (Week 1)	46.2 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 32	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 2 Day 1 (Week 3)	38.1 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 42	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 3 Day 1 (Week 6)	54.1 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 43	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 4 Day 1 (Week 9)	77.3 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 50	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 5 Day 1 (Week 12)	82.9 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 35	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 7 Day 1 (Week 18)	85.6 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 39	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 9 Day 1 (Week 24)	82.7 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 35	—	—
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab Cycle 13 Day 1 (Week 36)	97.7 Microgram per milliliter (µg/mL) Geometric Coefficient of Variation 23	—	—

SECONDARY outcome

Timeframe: C1 D8; C2 D1; C4 D1; C6 D1; C8 D1; C2 D8; C4 D8; C6 D8; C8 D8: Morning

Population: Zero participants were analyzed as no data collected for summary analysis.

PK was presented through graphical overlay comparison versus historic data. No numerical summary of data was intended or produced.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Predose Cycle 1 Day 1 through Follow Up (Up To 48 Months)

Population: All randomized participants who received at least 1 dose of study drug with both baseline and at least one post baseline ADA assessments.

Number of participants with positive treatment emergent anti-ramucirumab antibodies (ADA) was summarized by treatment group.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=74 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=37 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Number of Participants With Treatment-Emergent Anti-Ramucirumab Antibodies	3 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Baseline, Follow Up (Up To 48 Months)

Population: All randomized participants who received at least 1 dose of study drug with baseline and one post-baseline FACT-Hep Questionnaire.

FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180.Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=97 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=95 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=95 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) PWB	-2.75 Units on a Scale Standard Error 0.43	-2.88 Units on a Scale Standard Error 0.43	-1.65 Units on a Scale Standard Error 0.42
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) SWB	-0.26 Units on a Scale Standard Error 0.36	0.22 Units on a Scale Standard Error 0.36	0.56 Units on a Scale Standard Error 0.36
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) EWB	0.23 Units on a Scale Standard Error 0.31	0.64 Units on a Scale Standard Error 0.32	0.93 Units on a Scale Standard Error 0.31
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) FWB	-2.40 Units on a Scale Standard Error 0.44	-1.34 Units on a Scale Standard Error 0.44	-0.75 Units on a Scale Standard Error 0.44
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) HCS	-3.62 Units on a Scale Standard Error 0.63	-2.32 Units on a Scale Standard Error 0.64	-0.68 Units on a Scale Standard Error 0.63
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) FACT-Hep	-1.11 Units on a Scale Standard Error 0.37	-0.74 Units on a Scale Standard Error 0.37	-0.09 Units on a Scale Standard Error 0.37
Change From Baseline in Functional Assessment of Cancer Therapy Hepatobiliary Questionnaire (FACT-Hep) TOI	-8.68 Units on a Scale Standard Error 1.31	-6.43 Units on a Scale Standard Error 1.32	-3.01 Units on a Scale Standard Error 1.30

SECONDARY outcome

Timeframe: Baseline, Follow Up (Up To 48 Months)

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.

EQ-5D-5L is a 2-part questionnaire that assesses general health status for 'today'. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using country-specific algorithms, with scores ranging from less than 0 (where zero is a health state equivalent to death; negative values are valued as worse than dead) to 1 (perfect health). Index values were calculated using the US algorithm (-0.109 to 1). A higher score indicates better health state.

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=45 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=42 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=40 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score	0.61 Units on a Scale Standard Deviation 0.31	0.63 Units on a Scale Standard Deviation 0.29	0.66 Units on a Scale Standard Deviation 0.27

SECONDARY outcome

Timeframe: Baseline, Follow Up (Up To 48 Months)

Population: All randomized participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.

EQ-5D-5L is a 2-part questionnaire that assesses general health status 'today'. The second part is assessed using a VAS on which the patient rates their perceived health state, ranging from 0 millimeter (the worst health you can imagine) to 100 millimeter (the best health you can imagine).

Outcome measures

Outcome measures
Measure	8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=45 Participants Participants received 8 mg/kg ramucirumab plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for ramucirumab therapy).	80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine n=42 Participants Participants received 80 mg merestinib orally each day, plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on Days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for merestinib therapy).	Pooled Placebo n=40 Participants Participants received placebo IV and placebo oral (indistinguishable and equivalent volume to ramucirumab and merestinib) plus 25 mg/m² cisplatin and 1000 mg/m² gemcitabine IV on days 1 and 8, every 21 days (1 cycle). Participants may continue on study drug for up to 8 cycles (for cisplatin and gemcitabine therapy) or until disease progression, unacceptable toxicity, or other withdrawal criterion is met (for placebo therapy).
Change From Baseline in Participant-Reported EQ-5D-5L Visual Analog Scale (VAS) Score	66.44 millimeter (mm) Standard Deviation 22.8	66.57 millimeter (mm) Standard Deviation 21.73	69.08 millimeter (mm) Standard Deviation 20.03

Adverse Events

8 mg/kg Ramucirumab + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

Serious events: 53 serious events

Other events: 102 other events

Deaths: 84 deaths

Placebo IV + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

Serious events: 25 serious events

Other events: 49 other events

Deaths: 34 deaths

80 mg Merestinib + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

Serious events: 56 serious events

Other events: 100 other events

Deaths: 71 deaths

Placebo Oral + 25 mg/m² Cisplatin + 1000 mg/m² Gemcitabine

Serious events: 23 serious events

Other events: 48 other events

Deaths: 38 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 Other disclosure agreement is maximum of 10 years restriction on the PI that the sponsor can review results communications prior to public release and can embargo communications regarding trial results. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER