A Phase 1 Study in Patients With Solid Tumors | NCT01215916

NCT01215916

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
H8K-MC-JZAE	Other Identifier	Eli Lilly and Company

Status Module

Oversight Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Experimental: Pemetrexed followed by LY573636	Experimental	Pemetrexed on Day 1 followed by LY573636 on Day 4	Drug: LY573636 Drug: Pemetrexed
Experimental: LY573636 followed by Pemetrexed	Experimental	LY573636 on Day 1, pemetrexed on Day 4	Drug: LY573636 Drug: Pemetrexed
Experimental: LY573636 and Pemetrexed on Day 1	Experimental	LY573636 and Pemetrexed on Day 1	Drug: LY573636 Drug: Pemetrexed

Interventions

Name	Type	Description	Arm Group Labels	Other Names
LY573636	Drug	Individualized dose is dependent on a patient's height, weight, and gender and is adjusted to target a specific exposure range corrected for a patient's laboratory parameters. Intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Recommended Phase 2 Dose	Based on maximum tolerated dose (MTD) in Cycle 1: highest dose where <33% participants (pts) had dose-limiting toxicity (DLT). DLTs were adverse events (AE) possibly related to study drug or AEs that met any of National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTAE): Grade (G) 4 neutropenia lasting ≥5 days; G4 neutropenia with fever, G4 thrombocytopenia, G3 thrombocytopenia with bleeding, ≥G3 non-hematologic toxicity (except nausea/vomiting and diarrhea controlled by medication; electrolyte toxicity resolved with standard replacement treatment; alopecia; and elevated alanine aminotransferase or aspartate aminotransferase with preexisting hepatic metastasis, if agreed by investigator). Investigators, with sponsor, could declare a DLT if pt experienced increasing toxicity during treatment and it was clear that further treatment would expose pt to excessive risk. Enrollment was stopped during the dose-escalation phase, thus further dose-escalation was not explored.	Baseline to toxicity [up to end of Cycle 1 (cycle = 21 or 28 days)]

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Clinically Significant Effects	Clinically significant effects were defined as serious and other non-serious adverse events (AEs) regardless of causality. A summary of serious and all other non-serious AEs is located in the Reported Adverse Events module.	Baseline to end of study (up to 1 year of treatment plus 30-day follow-up)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

You must have a diagnosis of a solid tumor malignancy that is not amenable to curative therapy
You must have a serum albumin level greater than or equal to 3.0 grams per deciliter (g/dL) [30 grams per liter (g/L)]
You must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
You must be reliable and willing to make yourself available for the duration of the study and are willing to follow study procedures
Patients with reproductive potential should use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drugs
Your test results assessing the function of your blood, kidneys, liver, and heart are satisfactory
You must be willing to take folic acid, Vitamin B12, or prophylactic steroids
You must able to interrupt the use of aspirin (other than an aspirin dose less than or equal to 1.3 grams per day) and/or other nonsteroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days prior for long-acting agents, such as piroxicam)
You must have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, hormone therapy, or other investigational therapy for at least 4 weeks (6 weeks for mitomycin-C or nitrosoureas) before study enrollment and recovered from the acute effects of therapy (except alopecia). Patients who have received whole-brain radiation must wait 90 days before starting study therapy.
You must sign an informed consent

Exclusion Criteria:

You cannot have received other investigational drugs within the last 30 days
You cannot have other on-going serious illnesses including active bacterial, fugal, or viral infections
You cannot require regular, periodic paracentesis or thoracentesis
You cannot have active brain metastasis
You cannot currently be receiving warfarin (Coumadin®) therapy
You cannot be pregnant or lactating
You cannot have received prior pemetrexed or LY573636
You cannot have a second primary malignancy that could affect interpretation of the study results

Contacts/Locations Module

Name	Affiliation	Role
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon.-Fri. 9 AM - 5 PM Eastern Time (UTC/GMT - 5 hours, EST)	Eli Lilly and Company	Study Director

Locations

Facility	Status	City	State	ZIP	Country	Contacts
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.		New Brunswick	New Jersey	08901

Arm/Group Information

ID	Title	Description
FG000	LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day 1	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG001	LY573636, 340 µg/mL Plus Pemetrexed, 500 mg/m2 on Day 1	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL and 500 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG002	LY573636, 300 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG003	LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 375 mg/m2 on Day4	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 1 and 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG004	LY573636, 320 µg/mL on Day1 Plus Pemetrexed, 500 mg/m2 on Day4	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 1 and 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG005	Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 300 µg/mL on Day4	Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG006	Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4	Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG007	Pemetrexed, 500 mg/m2 on Day1 Plus LY573636, 320 µg/mL on Day4	Participants received a combination of 500 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 320 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.
FG008	Pemetrexed, 375 mg/m2 on Day1 Plus LY573636, 340 µg/mL on Day4	Participants received a combination of 375 mg/m2 of pemetrexed administered IV over 10 minutes on Day 1 and LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 340 µg/mL on day 4 of a 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG0001 subjects FG0015 subjects FG0023 subjects FG0036 subjects FG0046 subjects FG0054 subjects FG0069 subjects FG0073 subjects FG0082 subjects
Received at Least 1 Dose of Either Drug		FG0001 subjects FG0015 subjects FG0023 subjects FG0036 subjects
COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004
NOT COMPLETED		FG0001 subjects FG0015 subjects FG0023 subjects FG0036 subjects FG004

Type	Comment	Reasons
Progressive Disease		FG0000 subjects FG0012 subjects FG0021 subjects FG003

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day 1	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Recommended Phase 2 Dose	Based on maximum tolerated dose (MTD) in Cycle 1: highest dose where <33% participants (pts) had dose-limiting toxicity (DLT). DLTs were adverse events (AE) possibly related to study drug or AEs that met any of National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTAE): Grade (G) 4 neutropenia lasting ≥5 days; G4 neutropenia with fever, G4 thrombocytopenia, G3 thrombocytopenia with bleeding, ≥G3 non-hematologic toxicity (except nausea/vomiting and diarrhea controlled by medication; electrolyte toxicity resolved with standard replacement treatment; alopecia; and elevated alanine aminotransferase or aspartate aminotransferase with preexisting hepatic metastasis, if agreed by investigator). Investigators, with sponsor, could declare a DLT if pt experienced increasing toxicity during treatment and it was clear that further treatment would expose pt to excessive risk. Enrollment was stopped during the dose-escalation phase, thus further dose-escalation was not explored.	Enrollment was stopped during the dose-escalation phase and it was too early to assess the recommended dose for Phase 2 or to estimate the MTD, therefore zero participants were analyzed.	Posted						Baseline to toxicity [up to end of Cycle 1 (cycle = 21 or 28 days)]

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	LY573636, 300µg/mL Plus Pemetrexed, 375mg/m2 on Day1	Participants received a combination of LY573636 administered over a 2-hour intravenous (IV) infusion to target a Cmax of 300 µg/mL and 375 mg/m2 of pemetrexed administered IV over 10 minutes both on Day 1 of a 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or if any other withdrawal criteria were met.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment

Title	Organization	Phone	Extension	Email
Chief Medical Officer	Eli Lilly and Company	800-545-5979

ID	Term
C534068	N-((5-bromo-2-thienyl)sulfonyl)-2,4-dichlorobenzamide
D000068437	Pemetrexed

ID	Term
D006147	Guanine
D007042	Hypoxanthines
D011688	Purinones
D011687	Purines
D006574

ID	Title	Description
OG000	Pemetrexed Followed by LY573636	Pemetrexed on Day 1 and LY573636 on Day 4. LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 micrograms per milliliter (ug/mL) up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle. Pemetrexed: 375 milligrams per square meter (mg/m^2) to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle. Participants were pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent]. Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.
OG001	LY573636 Followed by Pemetrexed	LY573636 on Day 1 and pemetrexed on Day 4. LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 28-day cycle. Pemetrexed: 375 mg/m^2 to 500 mg/m^2; intravenous dosing was completed once each 28-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.
OG002	LY573636 and Pemetrexed on Day 1	LY573636 and pemetrexed on Day 1. LY573636: Individualized dosing was dependent on a participant's height, weight, and gender and was adjusted to target a specific LY573636 concentration corrected for a participant's laboratory parameters. The targeted drug concentration range for LY573636 dosing was 300 ug/mL up to 360 µg/mL. Intravenous dosing was completed once each 21-day cycle. Pemetrexed: 375 mg/m^2 to 500 mg/m^2. Intravenous dosing was completed once each 21-day cycle. Participants were pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent). Participants continued on study drug (LY573636 and pemetrexed) until disease progression, unacceptable toxicity, or other withdrawal criteria were met.