Advanced Cancer
Conditions
Keywords
Metastatic Cancer, Solid Tumors
Brief summary
The objective of this phase 1 study is to evaluate the safety and tolerability of Notch Inhibitor in participants with advanced cancer. This study includes dose escalation and dose confirmation components.
Interventions
DRUGLY900009 - Dose Escalation Phase (Part A)
2 milligrams (mg), 4 mg, 8 mg, 15 mg, 30 mg, 45 mg and 60mg LY900009 administered orally 3 times per week (Monday, Wednesday, Friday) for 4 weeks of a 28-day cycle. Participants experiencing clinical benefit may continue treatment unless discontinuation criteria are met.
DRUGLY900009 - Dose Confirmation Phase (Part B)
30 mg LY900009 orally 3 times per week (Monday, Wednesday, Friday) for 4 weeks of a 28-day cycle. Participants experiencing clinical benefit may continue treatment unless discontinuation criteria are met.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participants must be, in the judgment of the investigator, an appropriate candidate for experimental therapy after available standard therapies have ceased to provide clinical benefit for their disease. * The participants must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced and/or metastatic. * Have adequate organ function including: * Hematologic: Absolute neutrophil count (ANC) ≥1.5 x 10⁹/liter (L), platelets ≥100 x 10⁹/L, and hemoglobin ≥8 grams/deciliter (g/dL). * Hepatic: Bilirubin ≤1.5 times upper limits of normal (ULN) and alanine aminotransferase (ALT) ≤3.0 times ULN. * Renal: Serum creatinine ≤1.5 times ULN. * Have a performance status less than or equal to 1 for Dose Escalation and less than or equal to 2 for Dose Confirmation on the Eastern Cooperative Oncology Group (ECOG) scale. * Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (treatment-related toxicity resolved to baseline) except for residual alopecia. * Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug. * Females with childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study drug.
Exclusion criteria
* Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively. * Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (for example, inflammatory bowel disease or history of major surgical resection involving the stomach or small bowel). * Have malabsorptive syndromes, enteropathies, gastroenteritis (acute or chronic), or diarrhea (acute or chronic). * Females who are pregnant or lactating. * Have Central Nervous System (CNS) malignancy or metastasis. * Have an acute leukemia. * Have active bacterial, fungal and/or known viral infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Effects | Baseline to study completion up to 18.7 weeks | Clinically significant effects are study drug related serious adverse events (SAEs) and study drug related treatment emergent adverse events (TEAEs). A summary of all SAEs and all other non-SAEs regardless of causality is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Dose Range for Phase 2 Studies | Predose up to 28 days in Cycle 1 | Recommended Phase 2 dose was determined by the maximum tolerated dose (MTD). MTD is the highest dose with \<33% of participants having a dose-limiting toxicity (DLT) during Cycle 1. DLT is an adverse event (AE) occurring for a participant enrolled in Part A that is likely related to the study drug and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 4.02) Grade 3 or 4 nonhematologic toxicity except for Grade 3 nausea, vomiting or electrolyte disturbance; Grade 3 nausea, vomiting or electrolyte disturbance that persists more than 2 days despite maximal supportive intervention; Grade 4 hematological toxicity that persists more than 5 days; Grade 3 or 4 thrombocytopenia with bleeding; Grade 3 or 4 neutropenia with fever. A DLT can be declared if a participant experiences increasing toxicity during treatment. |
| Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | Baseline to measured progressive disease up to 15.1 weeks | Best overall response of stable disease or better is complete response (CR) + partial response (PR) + stable disease (SD) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (version 1.1). CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Percentage of Participants with a best overall response of SD or better is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated then multiplied by 100. |
| Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose | The geometric mean AUC(0-infinity) for each dose group is reported following a single dose of LY900009. |
| Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose | The geometric mean Cmax for each dose group is reported following a single dose of LY900009. |
Countries
United States
Participant flow
Pre-assignment details
Any participant who completed Cycle 1 or discontinued due to an adverse event (AE) in Part A is considered a completer. Any participant who completed cycle 1 or discontinued due to an AE or progressive disease in Part B was considered a completer.
Participants by arm
| Arm | Count |
|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) 2 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 3 |
| 4 mg LY900009 - Dose Escalation Phase (Part A) 4 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 4 |
| 8 mg LY900009 - Dose Escalation Phase (Part A) 8 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 3 |
| 15 mg LY900009 - Dose Escalation Phase (Part A) 15 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 3 |
| 30 mg LY900009 - Dose Escalation Phase (Part A) 30 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 6 |
| 45 mg LY900009 - Dose Escalation Phase (Part A) 45 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 5 |
| 60 mg LY900009 - Dose Escalation Phase (Part A) 60 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle. | 3 |
| 30 mg LY900009 - Dose Confirmation Phase (Part B) 30 mg LY900009 administered orally 3 times per week (every Monday, Wednesday, and Friday) for 4 weeks of a 28-day cycle | 8 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 3 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | 2 mg LY900009 - Dose Escalation Phase (Part A) | 4 mg LY900009 - Dose Escalation Phase (Part A) | 8 mg LY900009 - Dose Escalation Phase (Part A) | 15 mg LY900009 - Dose Escalation Phase (Part A) | 30 mg LY900009 - Dose Escalation Phase (Part A) | 45 mg LY900009 - Dose Escalation Phase (Part A) | 60 mg LY900009 - Dose Escalation Phase (Part A) | 30 mg LY900009 - Dose Confirmation Phase (Part B) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 5.5 | 54.0 years STANDARD_DEVIATION 9 | 66.0 years STANDARD_DEVIATION 14.2 | 57.3 years STANDARD_DEVIATION 13.6 | 62.5 years STANDARD_DEVIATION 8.6 | 58.4 years STANDARD_DEVIATION 21.9 | 55.7 years STANDARD_DEVIATION 13.7 | 57.5 years STANDARD_DEVIATION 9.8 | 58.8 years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 6 Participants | 5 Participants | 3 Participants | 7 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 4 Participants | 3 Participants | 2 Participants | 6 Participants | 5 Participants | 3 Participants | 7 Participants | 32 Participants |
| Region of Enrollment United States | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 6 Participants | 5 Participants | 3 Participants | 8 Participants | 35 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 3 Participants | 3 Participants | 4 Participants | 1 Participants | 2 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants | 1 Participants | 0 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 4 | 3 / 3 | 3 / 3 | 14 / 14 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 | 1 / 4 | 0 / 3 | 1 / 3 | 7 / 14 | 3 / 5 | 2 / 3 |
Outcome results
Primary
Number of Participants With Clinically Significant Effects
Clinically significant effects are study drug related serious adverse events (SAEs) and study drug related treatment emergent adverse events (TEAEs). A summary of all SAEs and all other non-SAEs regardless of causality is located in the Reported Adverse Events module.
Time frame: Baseline to study completion up to 18.7 weeks
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 2 Participants |
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 0 Participants |
| 4 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 1 Participants |
| 4 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 1 Participants |
| 8 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 3 Participants |
| 8 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 0 Participants |
| 15 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 0 Participants |
| 15 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 3 Participants |
| 30 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 0 Participants |
| 30 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 5 Participants |
| 45 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | SAEs | 0 Participants |
| 45 mg LY900009 - Dose Escalation Phase (Part A) | Number of Participants With Clinically Significant Effects | TEAEs | 5 Participants |
| 60 mg LY900009 - Part A: Dose Escalation | Number of Participants With Clinically Significant Effects | SAEs | 1 Participants |
| 60 mg LY900009 - Part A: Dose Escalation | Number of Participants With Clinically Significant Effects | TEAEs | 2 Participants |
| 30 mg LY900009 - Dose Confirmation Phase (Part B) | Number of Participants With Clinically Significant Effects | SAEs | 2 Participants |
| 30 mg LY900009 - Dose Confirmation Phase (Part B) | Number of Participants With Clinically Significant Effects | TEAEs | 6 Participants |
Secondary
Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity)
Best overall response of stable disease or better is complete response (CR) + partial response (PR) + stable disease (SD) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (version 1.1). CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Percentage of Participants with a best overall response of SD or better is calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated then multiplied by 100.
Time frame: Baseline to measured progressive disease up to 15.1 weeks
Population: All enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 33.3 percentage of participants |
| 4 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 0 percentage of participants |
| 8 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 66.7 percentage of participants |
| 15 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 33.3 percentage of participants |
| 30 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 16.7 percentage of participants |
| 45 mg LY900009 - Dose Escalation Phase (Part A) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 0 percentage of participants |
| 60 mg LY900009 - Part A: Dose Escalation | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 0 percentage of participants |
| 30 mg LY900009 - Dose Confirmation Phase (Part B) | Percentage of Participants With a Best Overall Response of Stable Disease or Better (Document the Antitumor Activity) | 0 percentage of participants |
Secondary
Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)]
The geometric mean AUC(0-infinity) for each dose group is reported following a single dose of LY900009.
Time frame: Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose
Population: All enrolled participants who received the study drug and had sufficient pharmacokinetic (PK) data to calculate AUC(0-infinity).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | NA nanograms*hour/milliliters (ng*h/mL) | — |
| 4 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 31.6 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 48 |
| 8 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 76.2 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 123 |
| 15 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 121 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 59 |
| 30 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 315 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 71 |
| 45 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 547 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 32 |
| 60 mg LY900009 - Part A: Dose Escalation | Pharmacokinetics: Area Under the Concentration-time Curve of LY900009 From Time Zero to Infinity [AUC(0-infinity)] | 1240 nanograms*hour/milliliters (ng*h/mL) | Geometric Coefficient of Variation 53 |
Secondary
Pharmacokinetics: Maximum Concentration (Cmax) of LY900009
The geometric mean Cmax for each dose group is reported following a single dose of LY900009.
Time frame: Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose
Population: All enrolled participants who received the study drug and had sufficient pharmacokinetic (PK) data to calculate Cmax.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 4.03 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 122 |
| 4 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 11.7 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 70 |
| 8 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 20.2 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 68 |
| 15 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 27.4 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 50 |
| 30 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 71.2 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 104 |
| 45 mg LY900009 - Dose Escalation Phase (Part A) | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 96.2 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| 60 mg LY900009 - Part A: Dose Escalation | Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | 158 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
Secondary
Recommended Dose Range for Phase 2 Studies
Recommended Phase 2 dose was determined by the maximum tolerated dose (MTD). MTD is the highest dose with \<33% of participants having a dose-limiting toxicity (DLT) during Cycle 1. DLT is an adverse event (AE) occurring for a participant enrolled in Part A that is likely related to the study drug and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 4.02) Grade 3 or 4 nonhematologic toxicity except for Grade 3 nausea, vomiting or electrolyte disturbance; Grade 3 nausea, vomiting or electrolyte disturbance that persists more than 2 days despite maximal supportive intervention; Grade 4 hematological toxicity that persists more than 5 days; Grade 3 or 4 thrombocytopenia with bleeding; Grade 3 or 4 neutropenia with fever. A DLT can be declared if a participant experiences increasing toxicity during treatment.
Time frame: Predose up to 28 days in Cycle 1
Population: All enrolled participants who received at least one dose of study drug during dose escalation phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2 mg LY900009 - Dose Escalation Phase (Part A) | Recommended Dose Range for Phase 2 Studies | 30 milligrams (mg) |