T-cell Acute Lymphoblastic Leukemia, T-cell Lymphoblastic Lymphoma
Conditions
Brief summary
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).
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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* Have previously completed or withdrawn from this study or any other study investigating LY3039478 or other Notch inhibitors.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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (Up To 28 Days) | 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). |
| Recommended Dose of LY3039478 in Combination With Dexamethasone | Cycle 1 (28 Days) | 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. |
| Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | Baseline to Objective Disease Progression (Up To 2 Months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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\[0-∞\]) of LY3039478 in Combination with Dexamethasone in Day 1 |
| 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) | — |
| Phase 2:Relapse Free Survival (RFS) | Date of CR to Relapse or Death from any Cause (Approximately 1 Year) | — |
| 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 | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC\[0- 48\]) of LY3039478 in Combination with Dexamethasone in Day 8 |
| Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | Baseline to Objective Disease Progression (Up To 12 Months) | 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. |
Countries
France, Germany, Israel, Italy, United States
Participant flow
Pre-assignment details
Study completers are those participants that completed Part A cycle 1 or experienced a DLT. There were no participants enrolled to Part B and Phase 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| 50 mg LY3039478 + Dexamethasone 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. | 6 |
| 75 mg LY3039478 + Dexamethasone Part A: 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. | 12 |
| 100 mg LY3039478 + Dexamethasone Part A: 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. | 15 |
| 125 mg LY3039478 + Dexamethasone Part A: 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. | 3 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 0 |
| Overall Study | Death | 1 | 2 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 1 | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | 75 mg LY3039478 + Dexamethasone | 100 mg LY3039478 + Dexamethasone | 50 mg LY3039478 + Dexamethasone | 125 mg LY3039478 + Dexamethasone | Total |
|---|---|---|---|---|---|
| Age, Continuous | 36.42 years STANDARD_DEVIATION 13.4 | 45.87 years STANDARD_DEVIATION 14.41 | 38.83 years STANDARD_DEVIATION 12.22 | 26.67 years STANDARD_DEVIATION 10.69 | 39.94 years STANDARD_DEVIATION 14.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 11 Participants | 4 Participants | 2 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 10 Participants | 12 Participants | 5 Participants | 3 Participants | 30 Participants |
| Region of Enrollment France | 4 Participants | 4 Participants | 3 Participants | 0 Participants | 11 Participants |
| Region of Enrollment Germany | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Italy | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 7 Participants | 7 Participants | 2 Participants | 1 Participants | 17 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 0 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 6 Participants | 2 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 8 / 12 | 12 / 15 | 2 / 3 |
| other Total, other adverse events | 6 / 6 | 12 / 12 | 15 / 15 | 3 / 3 |
| serious Total, serious adverse events | 6 / 6 | 11 / 12 | 9 / 15 | 3 / 3 |
Outcome results
Primary
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.
Time frame: Baseline to Objective Disease Progression (Up To 2 Months)
Population: All participants who received at least one dose of study drug in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | 1 Participants |
| 75 mg LY3039478 + Dexamethasone | Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | 0 Participants |
| 100 mg LY3039478 + Dexamethasone | Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | 0 Participants |
| 125 mg LY3039478 + Dexamethasone | Number of Participants Who Achieve Complete Remission (CR) or CR With Incomplete Blood Count Recovery (CRi): Overall Remission Rate (ORR) | 0 Participants |
Primary
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).
Time frame: Cycle 1 (Up To 28 Days)
Population: All participants who received at least one dose of study drug in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| 75 mg LY3039478 + Dexamethasone | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| 100 mg LY3039478 + Dexamethasone | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| 125 mg LY3039478 + Dexamethasone | Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
Primary
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.
Time frame: Cycle 1 (28 Days)
Population: All participants who received at least one dose of study drug in Part A.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Recommended Dose of LY3039478 in Combination With Dexamethasone | 75 mg |
Secondary
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.
Time frame: Baseline to Objective Disease Progression (Up To 12 Months)
Population: All participants who received at least one dose of study drug in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | 0 Participants |
| 75 mg LY3039478 + Dexamethasone | Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | 0 Participants |
| 100 mg LY3039478 + Dexamethasone | Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | 0 Participants |
| 125 mg LY3039478 + Dexamethasone | Number of Participants With CR or CRi and Notch-1 or FBXW7 Mutations | 0 Participants |
Secondary
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
Time frame: Cycle 1 Day 8: Predose, 1-2, 3-4,6-8,24-30 hours
Population: All participants who received at least one dose of study drug in Part A and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination With Dexamethasone in Day 8 | 3050 ng*h/mL | Geometric Coefficient of Variation 18 |
| 75 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination With Dexamethasone in Day 8 | 4070 ng*h/mL | Geometric Coefficient of Variation 92 |
| 100 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination With Dexamethasone in Day 8 | 4640 ng*h/mL | Geometric Coefficient of Variation 55 |
| 125 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0- 48]) of LY3039478 in Combination With Dexamethasone in Day 8 | 8240 ng*h/mL | — |
Secondary
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
Time frame: Cycle 1 Day 1: Predose, 1-2, 3-4,6-8,24-30 hours
Population: All participants who received at least one dose of study drug in Part A and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 50 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination With Dexamethasone in Day 1 | 3480 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 26 |
| 75 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination With Dexamethasone in Day 1 | 5000 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 45 |
| 100 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination With Dexamethasone in Day 1 | 5870 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 49 |
| 125 mg LY3039478 + Dexamethasone | Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC[0-∞]) of LY3039478 in Combination With Dexamethasone in Day 1 | 6330 nanogram hour per milliliter (ng*h/mL) | — |
Secondary
Phase 2: Change From Baseline in the Functional Assessment of Cancer Therapy-Leukemia-General (FACT-Leu-G) Score
Time frame: Baseline, End of Study (Approximately 1.5 Years)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2: Duration of Remission (DoR)
Time frame: Date of CR, CRi, or PR to Date of Relapse or Death from Any Cause (Approximately 1 Year)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2: Event Free Survival (EFS)
Time frame: Baseline to Objective Disease Progression or Death from Any Cause (Approximately 1 Year)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2: Number of Participants Who Achieve CR, CRi or Partial Remission (PR): Overall Remission Rate (ORR) Plus PR
Time frame: Baseline to Objective Disease Progression (Up To 12 Months)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2: Number of Participants Who Achieve PR
Time frame: Baseline to Objective Disease Progression (Up To 12 Months)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2: Overall Survival (OS)
Time frame: Baseline to the Date of Death from Any Cause (Approximately 1.5 Years)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.
Secondary
Phase 2:Relapse Free Survival (RFS)
Time frame: Date of CR to Relapse or Death from any Cause (Approximately 1 Year)
Population: Zero participants analyzed. There were no participants enrolled in Phase 2 of the study.