A Study of LY3039478 in Combination With Dexamethasone in Participants With T-ALL/T-LBL

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety of the study drug known as LY3039478 in combination with dexamethasone in participants with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma (T-ALL/T-LBL).

Official Title
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A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination With Dexamethasone in T-ALL/T-LBL Patients

Conditions
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T-cell Acute Lymphoblastic Leukemia, T-cell Lymphoblastic Lymphoma

Intervention / Treatment
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* Drug: LY3039478
* Drug: Dexamethasone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have acute T-cell lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). T-ALL or T-LBL participants with relapsed/refractory disease. Have had at least 60 days between prior hematopoietic stem cell transplantation (SCT) and first dose of study drug. Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale for adults. Lansky score >50% for participants <16 years old. Have adequate organ function. Are at least: adult Phase 1 Part A and Phase 2: ≥16 years old at the time of screening pediatric Phase 1 Part B: 2 to <16 years old Men and women with reproductive potential: Must agree to use a reliable method of birth control during the study and for 3 months following the last dose of study drug(s) or country requirements, whichever is longer. Females with childbearing potential: Have had a negative serum pregnancy test ≤7 days before the first dose of study drug and also must not be breastfeeding. Are able to swallow capsules and tablets. Exclusion Criteria: Have previously completed or withdrawn from this study or any other study investigating LY3039478 or other Notch inhibitors. Have evidence of uncontrolled, active infection <7 days prior to administration of study medication. Have current or recent gastrointestinal disease with chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Have active leukemic involvement of the central nervous system (CNS).

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3039478 + Dexamethasone (Adult)<br>Part A: 50 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. 75 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. 100 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. 125 mg LY3039478 administered orally three times per week (TIW) and 24 mg dexamethasone administered orally on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. | Drug: LY3039478<br>* Administered orally<br>Drug: Dexamethasone<br>* Administered orally<br>|
| Experimental: LY3039478 + Dexamethasone (Pediatric)<br>Part B: LY3039478 administered orally TIW at escalating doses and dexamethasone administered orally twice a day (BID) on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. There were no participants enrolled to Part B of the study. | Drug: LY3039478<br>* Administered orally<br>Drug: Dexamethasone<br>* Administered orally<br>|
| Experimental: Phase 2: LY3039478 + Dexamethasone<br>LY3039478 administered orally TIW and dexamethasone administered orally BID on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. There were no participants enrolled to Phase 2 of the study. | Drug: LY3039478<br>* Administered orally<br>Drug: Dexamethasone<br>* Administered orally<br>|
| Placebo Comparator: Phase 2: Placebo + Dexamethasone<br>Placebo administered orally TIW and dexamethasone administered orally BID on days 1-5 every other week during 28 day cycles. Participants receiving benefit may continue until disease progression. There were no participants enrolled to Phase 2 of the study. | Drug: Dexamethasone<br>* Administered orally<br>Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | A DLT was an Adverse Event(AE) observed during the first 28 day cycle that is determined by the investigator to be at least possibly related to LY3039478 according to CTCAE v 4.0 and fulfills any of the following criteria: CTCAE Grade 3 nonhematological toxicity with a few exceptions, any other significant toxicity deemed to be dose limiting (eg, any toxicity that is possibly related to the study medication that requires the withdrawal of the patient from the study during Cycle 1). | Cycle 1 (Up To 28 Days) | 
| Recommended Dose of LY3039478 in Combination With Dexamethasone | A DLT was an Adverse Event(AE) observed during the first 28 day cycle that is determined by the investigator to be at least possibly related to LY3039478 according to CTCAE v 4.0 and fulfills any of the following criteria:CTCAE Grade 3 nonhematological toxicity with a few exceptions, any other significant toxicity deemed to be dose limiting.A dose-limiting equivalent toxicity (DLET) was defined as an AE occurring between Day 1 and Day 28 of any cycle (other than Cycle 1) for a patient enrolled in the Phase 1 portion or in any cycle (including Cycle 1) for a patient enrolled in the Phase 2 portion that would have met the criteria for DLT if it had occurred during Cycle 1 for a patient enrolled in the Phase 1 portion. | Cycle 1 (28 Days) | 
| Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | ORR is defined as the number of participants who achieved a best overall response of either complete remission (CR) or incomplete remission (CRi). The ORR (CR and CRi) is the sum of patients achieving a CR or a CRi divided by the total number of patients randomized in that arm. CR is defined as the number of participants who achieved a best overall response of complete remission (CR), out of the total number of participants randomized in that arm. | Baseline to Objective Disease Progression (Up To 2 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination With Dexamethasone in Day 1 | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination with Dexamethasone in Day 1 | Cycle 1 Day 1: Predose, 1-2, 3-4,6-8,24-30 hours | 
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination With Dexamethasone in Day 8 | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination with Dexamethasone in Day 8 | Cycle 1 Day 8: Predose, 1-2, 3-4,6-8,24-30 hours | 
| Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | ORR is defined as the number of participants who achieved a best overall response of either complete remission (CR) or incomplete remission (CRi). The ORR (CR and CRi) is the sum of participants achieving a CR or a CRi divided by the total number of participants randomized in that arm. CR is defined as the number of participants who achieved a best overall response of complete remission (CR), out of the total number of participants randomized in that arm. | Baseline to Objective Disease Progression (Up To 12 Months) | 
| Phase 2: Number of Participants Who Achieve CR, CRi or Partial Remission (PR): Overall Remission Rate (ORR) Plus PR |  | Baseline to Objective Disease Progression (Up To 12 Months) | 
| Phase 2: Number of Participants Who Achieve PR |  | Baseline to Objective Disease Progression (Up To 12 Months) | 
| Phase 2: Duration of Remission (DoR) |  | Date of CR, CRi, or PR to Date of Relapse or Death from Any Cause (Approximately 1 Year) | 
| Phase 2:Relapse Free Survival (RFS) |  | Date of CR to Relapse or Death from any Cause (Approximately 1 Year) | 
| Phase 2: Event Free Survival (EFS) |  | Baseline to Objective Disease Progression or Death from Any Cause (Approximately 1 Year) | 
| Phase 2: Overall Survival (OS) |  | Baseline to the Date of Death from Any Cause (Approximately 1.5 Years) | 
| Phase 2: Change From Baseline in the Functional Assessment of Cancer Therapy-Leukemia-General (FACT-Leu-G) Score |  | Baseline, End of Study (Approximately 1.5 Years) |