A Study of LY2603618 in Combination With Gemcitabine in Participants With Solid Tumors

A Phase 1 Dose-Escalation Study of LY2603618 in Combination With Gemcitabine in Japanese Patients With Solid Tumors

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01341457

Enrollment

Registered

2011-04-25

Start date

2011-05-31

Completion date

2016-07-31

Last updated

2019-03-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Solid Tumors

Brief summary

The primary objective of this study is to evaluate the safety and tolerability of LY2603618 in combination with the standard dose of gemcitabine up to the global recommended dose of LY2603618 in Japanese participants with solid advanced or metastatic tumors.

Interventions

DRUGLY2603618

Administered intravenously

DRUGGemcitabine

Administered intravenously

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Have histological or cytological or imaging evidence of a diagnosis of cancer that is advanced and/or metastatic disease * Participant who is planned to have gemcitabine therapy at the proposed doses because he/she was not able to benefit from standard therapy and/or therapies known to provide clinical benefit or there is no standard therapy for the advanced and/or metastatic disease globally * Have given written informed consent prior to any study-specific procedures * Have adequate hematologic, hepatic and renal function * Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale * Have discontinued all previous therapies for cancer, including chemotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 30 days (42 days for mitomycin C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy * Prior radiation therapy for treatment of cancer is allowed to less than 25% of the bone marrow, and participants must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 30 days prior to study enrollment * Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the study and for 3 months after the last infusion of study drug * Females with child bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have had a negative urine pregnancy test less than 7 days prior to the enrollment * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures * Have an estimated life expectancy of at least 12 weeks

Exclusion criteria

* Are currently enrolled in, or discontinued within the last 30 days from, a clinical study involving an off-label use of an investigational drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have serious preexisting medical conditions or serious concomitant systemic disorders that would compromise the safety of the participant or his/her ability to complete the study * Have interstitial pneumonitis or pulmonary fibrosis, or previous history of them * Have symptomatic central nervous system malignancy or metastasis * Have current active infection * Females who are pregnant or lactating * Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb) * Participants with acute or chronic leukemia or with any other disease likely to have a significant bone marrow infiltration * Have previously completed or withdrawn from this study or any other study investigating LY2603618 or any other checkpoint kinase (Chk1) inhibitor * Have known allergy to gemcitabine or LY2603618 or any ingredient of gemcitabine or LY2603618 (like Captisol®) * Have an abnormal electrocardiogram (ECG) result that would put the participant at unnecessary risk in the opinion of the investigator

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose Limiting Toxicity (DLT)	Cycle 1 (28 Days)	DLT is defined as adverse event (AE) during Cycle 1 (Days 1 through 28) that was possibly related to the study drug and toxicities considered by the investigator as dose limiting. A summary of other nonserious AEs, and all serious adverse events (SAE's), regardless of causality, is located in the Reported Adverse Events section.

Secondary

Measure	Time frame	Description
Number of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Best Overall Response)	Baseline to Measured Progressive Disease (Up to 52 Months)	Participants achieved disease control if they had a best overall response of PR, CR or SD according to RECIST v1.1 (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); PR at least 30% decrease and PD at least 20% increase in the sum of diameter of target lesions; CR: disappearance of all target lesions). Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Best response of SD is defined as disease that does not meet the criteria for CR, PR or PD and has been evaluated at least 6 weeks after the first gemcitabine administration.
PK: Area Under the Plasma Concentration vs. Time Curve From Time Zero to Infinity [AUC(0-∞)] of LY2603618	Cycle 1 (days 2 and 16) & 2 (day 2): Predose, End of Infusion, 1 hour (h), 3h, 6h, 24h (days 3 and 17), 48h (days 4 and 18 cycle 1 only), 72h (days 5 and 19)	—
PK: Cmax of Gemcitabine	Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m	—
Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of LY2603618	Cycle 1 (days 2 and 16) & 2 (day 2): Predose, End of Infusion, 1 hour (h), 3h, 6h, 24h (days 3 and 17), 48h (days 4 and 18 cycle 1 only), 72h (days 5 and 19)	—
PK: AUC(0-∞) of Gemcitabine	Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m	—
PK: AUC(0-∞) of Gemcitabine Metabolite dFdU	Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m	—
PK: Cmax of Gemcitabine Metabolite Deoxydifluorouridine (dFdU)	Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m	—

Countries

Japan

Participant flow

Pre-assignment details

Participant study completion is defined as a participant completing the primary and secondary objective assessments.

Participants by arm

Arm	Count
170 mg LY2603618 + Gemcitabine Gemcitabine 1000 milligrams per meter squared (mg/m²) administered intravenously (IV) on days 1, 8 and 15 of at least one 28-day cycle. 170 mg LY2603628 administered IV on days 2, 9 and 16 of at least one 28-day cycle. Participants experiencing benefit may continue on the combination therapy until discontinuation criteria are met.	7
230 mg LY2603618 + Gemcitabine Gemcitabine 1000 mg/m² administered IV on days 1, 8 and 15 of at least one 28-day cycle. 230 mg LY2603628 administered IV on days 2, 9 and 16 of at least one 28-day cycle. Participants experiencing benefit may continue on the combination therapy until discontinuation criteria are met.	10
Total	17

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	2	0

Baseline characteristics

Characteristic	170 mg LY2603618 + Gemcitabine	Total	230 mg LY2603618 + Gemcitabine
Age, Continuous	62.1 years STANDARD_DEVIATION 9.33	61.3 years STANDARD_DEVIATION 7.69	60.8 years STANDARD_DEVIATION 6.81
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	17 Participants	10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	7 Participants	17 Participants	10 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	0 Participants	0 Participants
Region of Enrollment Japan	7 Participants	17 Participants	10 Participants
Sex: Female, Male Female	6 Participants	7 Participants	1 Participants
Sex: Female, Male Male	1 Participants	10 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	7 / 7	10 / 10
serious Total, serious adverse events	0 / 7	2 / 10

Outcome results

Primary

Number of Participants With Dose Limiting Toxicity (DLT)

DLT is defined as adverse event (AE) during Cycle 1 (Days 1 through 28) that was possibly related to the study drug and toxicities considered by the investigator as dose limiting. A summary of other nonserious AEs, and all serious adverse events (SAE's), regardless of causality, is located in the Reported Adverse Events section.

Time frame: Cycle 1 (28 Days)

Population: Participants who completed the first cycle of study treatment or who discontinued study treatment due to a DLT. There was one participant in the 170 mg LY2603618 treatment group that had an insufficient number of doses of gemcitabine to evaluate DLT.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
170 mg LY2603618 + Gemcitabine	Number of Participants With Dose Limiting Toxicity (DLT)	1 Participants
230 mg LY2603618 + Gemcitabine	Number of Participants With Dose Limiting Toxicity (DLT)	2 Participants

Secondary

Number of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Best Overall Response)

Participants achieved disease control if they had a best overall response of PR, CR or SD according to RECIST v1.1 (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); PR at least 30% decrease and PD at least 20% increase in the sum of diameter of target lesions; CR: disappearance of all target lesions). Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Best response of SD is defined as disease that does not meet the criteria for CR, PR or PD and has been evaluated at least 6 weeks after the first gemcitabine administration.

Time frame: Baseline to Measured Progressive Disease (Up to 52 Months)

Population: All randomized participants who received at least one dose of study drug and had measurable lesion(s).

Arm	Measure	Value (NUMBER)
170 mg LY2603618 + Gemcitabine	Number of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Best Overall Response)	2 participants
230 mg LY2603618 + Gemcitabine	Number of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Best Overall Response)	5 participants

Secondary

Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of LY2603618

Time frame: Cycle 1 (days 2 and 16) & 2 (day 2): Predose, End of Infusion, 1 hour (h), 3h, 6h, 24h (days 3 and 17), 48h (days 4 and 18 cycle 1 only), 72h (days 5 and 19)