Notch Inhibitor in Advanced Cancer

Study Overview
=================
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.

Official Title
-----------------
Phase 1 Study of a Notch Inhibitor in Patients With Advanced Cancer

Conditions
-----------------
Advanced Cancer

Intervention / Treatment
-----------------
* Drug: LY900009 - Dose Escalation Phase (Part A)
* Drug: LY900009 - Dose Confirmation Phase (Part B)


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY900009<br>Dose escalation phase: 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. Dose confirmation phase: 30 mg 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. | Drug: LY900009 - Dose Escalation Phase (Part A)<br>* 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.<br>* Other names: Notch Inhibitor;Drug: LY900009 - Dose Confirmation Phase (Part B)<br>* 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.<br>* Other names: Notch Inhibitor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to study completion up to 18.7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Predose up to 28 days in Cycle 1 | 
| 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. | Baseline to measured progressive disease up to 15.1 weeks | 
| 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. | Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose | 
| Pharmacokinetics: Maximum Concentration (Cmax) of LY900009 | The geometric mean Cmax for each dose group is reported following a single dose of LY900009. | Day1: Pre-dose, 0.5 hours (hr), 1 hr, 3-4 hr, 6-8 hr and 24-30 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Metastatic Cancer, Solid Tumors