Trial Outcomes & Findings for A Dose Escalation Study of Adavosertib(MK1775) in Combination With 5-FU or 5-FU/CDDP in Patients With Advanced Solid Tumor (1775-005 (NCT NCT01047007)

Last Updated: 2023-09-21

Results Overview

DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity preventing treatment for ≥3 weeks or preventing administration of ≥8 of 10 doses in Parts 1 or 2A1 or 4 of 5 doses in Part 2A2.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

11 participants

Primary outcome timeframe

Cycle 1 (21 days)

Results posted on

2023-09-21

Participant Flow

This study enrolled participants with a confirmed locally advanced or metastatic solid tumor failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Additional inclusion and exclusion criteria applied.

Participants received MK-1775 (Part 1), MK-1775 + 5-Fluorouracil (Part 2A), and MK-1775 + 5-Fluorouracil and cis-diamminedichloroplatinum (Parts 2B and 3). The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-Fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) regimen.

Participant milestones

Participant milestones
Measure	Part 1: MK-1775 65 mg BID Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle.	Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle.	Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle.
Overall Study STARTED	3	6	2
Overall Study Treated	3	6	2
Overall Study COMPLETED	1	0	0
Overall Study NOT COMPLETED	2	6	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: MK-1775 65 mg BID Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle.	Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle.	Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle.	Parts 2B +3: MK-1775 + 5-FU + CDDP Participants were to receive 20 mg or 65 mg of MK-1775 administered either BID or QD on Days 1-5 of a 21-day cycle; 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle; and 60 mg/m\^2 to 100 mg/m\^2 of CDDP administered as an IV infusion on Day 1.
Overall Study Adverse Event	0	2	1	0
Overall Study Progressive Disease	2	4	1	0

Baseline Characteristics

A Dose Escalation Study of Adavosertib(MK1775) in Combination With 5-FU or 5-FU/CDDP in Patients With Advanced Solid Tumor (1775-005

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: MK-1775 65 mg BID n=3 Participants Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle.	Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg n=6 Participants Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle.	Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg n=2 Participants Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle.	Parts 2B +3: MK-1775 + 5-FU + CDDP Participants were to receive 20 mg or 65 mg of MK-1775 administered either BID or QD on Days 1-5 of a 21-day cycle; 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle; and 60 mg/m\^2 to 100 mg/m\^2 of CDDP administered as an IV infusion on Day 1.	Total n=11 Participants Total of all reporting groups
Age, Continuous	63.0 Years STANDARD_DEVIATION 4.4 • n=5 Participants	62.7 Years STANDARD_DEVIATION 7.9 • n=7 Participants	59.0 Years STANDARD_DEVIATION 5.7 • n=5 Participants	—	62.1 Years STANDARD_DEVIATION 6.4 • n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	—	1 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	—	10 Participants n=21 Participants
ECOG Performance Status ECOG Score = 0	2 Participants n=5 Participants	3 Participants n=7 Participants	2 Participants n=5 Participants	—	7 Participants n=21 Participants
ECOG Performance Status ECOG Score = 1	1 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	—	4 Participants n=21 Participants
Number of Prior Chemotherapy Regimens	2.0 Prior regimens STANDARD_DEVIATION 0.0 • n=5 Participants	3.3 Prior regimens STANDARD_DEVIATION 0.8 • n=7 Participants	4.0 Prior regimens STANDARD_DEVIATION 0.0 • n=5 Participants	—	3.1 Prior regimens STANDARD_DEVIATION 0.9 • n=21 Participants

PRIMARY outcome

Timeframe: Cycle 1 (21 days)

Population: The DLT-evaluable population consisted of participants who received at least one dose of MK-1775 and completed Cycle 1 of Parts 1, 2A1, 2A2, or discontinued due to toxicity.

Outcome measures

Outcome measures
Measure	Part 1: MK-1775 65 mg BID n=3 Participants Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle.	Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg n=6 Participants Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle.	Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg n=2 Participants Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle.	Parts 2B +3: MK-1775 + 5-FU + CDDP Participants were to receive 20 mg or 65 mg of MK-1775 administered either BID or QD on Days 1-5 of a 21-day cycle; 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle; and 60 mg/m\^2 to 100 mg/m\^2 of CDDP administered as an IV infusion on Day 1.
Number of Participants With Dose Limiting Toxicities (DLTs)	0 Participants	1 Participants	1 Participants	—

PRIMARY outcome

Timeframe: Cycle 1 (21 days)

Population: Participants who received at least one dose of MK-1775 in combination with 5-FU/CDDP and completed Cycle 1 of Parts 2B and 3. No participants received the 5-FU/CDDP regimen due to early termination of the study.

The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic esophageal, head and neck, or gastric cancer was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Cycle 1 (21 days)

The maximum tolerated dose (MTD) of MK-1775 in combination with 5-FU/CDDP for participants with locally advanced or metastatic solid tumors was determined based on DLTs that occurred during Cycle 1 of Parts 2B and 3. The MTD for MK-1775 in combination with 5-FU/CDDP was defined as the dose level at which approximately 30% of the participants were expected to experience a DLT for the combination therapy. The study was terminated early and Parts 2B and 3 were not performed. No participants received the 5-FU/CDDP regimen therefore the MTD for MK-1775 in combination with 5-FU/CDDP was not established.

Outcome measures

Outcome data not reported

Adverse Events

Part 1: MK-1775 65 mg BID

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Part 1: MK-1775 65 mg BID n=3 participants at risk Participants received 65 mg of MK-1775 administered orally twice a day (BID) on Days 1-5 of a 21-day cycle.	Part 2 A1: MK-1775 20 mg BID + 5-FU 1000 mg n=6 participants at risk Participants received 20 mg of MK-1775 administered orally BID on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an intravenous (IV) infusion on Days 1-4 of a 21-day cycle.	Part 2 A2: MK-1775 20 mg QD + 5-FU 1000 mg n=2 participants at risk Participants received 20 mg of MK-1775 administered orally once a day (QD) on Days 1-5 of a 21-day cycle and 1000 mg/m\^2/day of 5-FU administered as an IV infusion on Days 1-4 of a 21-day cycle.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/3 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	0.00% 0/6 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	50.0% 1/2 • Number of events 1 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.
Nervous system disorders Encephalopathy	0.00% 0/3 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	16.7% 1/6 • Number of events 1 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	0.00% 0/2 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.
Respiratory, thoracic and mediastinal disorders Pulmonary fistula	0.00% 0/3 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	16.7% 1/6 • Number of events 1 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.	0.00% 0/2 • From first dose of MK-1775 alone or in combination with 5-FU through follow-up; up to 7 months AEs for all participants who received at least one dose of MK-1775 alone or in combination with 5-FU.

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication guidelines.
Publication restrictions are in place

Restriction type: OTHER