A Phase 1b/Randomized Phase 2 Study to Evaluate LY3039478 in Combination with Dexamethasone in T-cell Lymphoblastic Leukemia (T-ALL) or T-cell Lymphoblastic Lymphoma(T-LBL) Patients
The goal of this clinical research study is to learn if LY3039478 given in combination with dexamethasone can help to control relapsed and/or refractory T-LBL or T-ALL.
Disease Group: Leukemia
Treatment Agent: Dexamethasone,LY3039478
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Eli Lilly and Company
The primary objective is as follows: Phase 1: To determine the recommended dose of LY3039478 in combination with dexamethasone in adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) (Part A) and pediatric patients (Part B). The Department of Leukemia will participate in Part A only of this study. Phase 2: To determine if the overall remission rate (ORR) (CR plus CR with incomplete blood count recovery [CRi]) in adult patients with relapsed/refractory T-ALL/T-LBL treated with LY3039478 in combination with dexamethasone exceeds that of those patients treated with placebo in combination with dexamethasone The secondary objectives are as follows: Phase 1: To characterize the safety and toxicity profile of LY3039478 in combination with dexamethasone as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 To assess the pharmacokinetic (PK) parameters of LY3039478 in combination with dexamethasone therapy To document efficacy based on Cheson criteria for leukemia and modified response criteria for malignant lymphoma To evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy Phase 2: To compare the ORR plus partial remission (PR) and PR alone for both arms To assess the remission rate for patients receiving LY3039478 in combination with dexamethasone after failure of placebo in combination with dexamethasone To assess duration of remission (DoR) (= CR and Cri and PR) To assess relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) To compare the safety and toxicity profile of LY3039478 in combination with dexamethasone to dexamethasone and placebo as assessed by NCI CTCAE v 4.0 To assess the pharmacokinetic (PK) parameters of LY3039478 and dexamethasone in combination therapy To assess patient quality of life using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) To evaluate gene mutation (eg, NOTCH-1/FBXW7/RAS/PTEN) status with efficacy The exploratory objectives are as follows: To assess clinical utility of the NICD immunohistochemistry (IHC) assay as a potential companion diagnostic for LY3039478 To evaluate biomarkers in tumor tissue, blood, plasma, and cerebrospinal fluid (CSF), which may include, but not be limited to, NICD enzyme-linked immunosorbent assay (ELISA) (or an alternative validated method), gene expression, relevant to the study disease or safety, efficacy, and mechanism of action of LY3039478 and dexamethasone To explore pharmacodynamic (PD) effects of LY3039478 on biomarkers indicative of Notch activity To evaluate the CSF exposure of LY3039478
IRB Review and Approval Date: 10/02/2015
Recruitment Status: Open
Projected Accrual: 86-92
1) Have acute T-cell lymphoblastic leukemia (T-ALL) or T-cell
lymphoblastic lymphoma (T-LBL). T-ALL is defined by >/=25% of blasts
in the bone marrow and expression of at least 2 of the following cell
surface antigens: CD1a, CD2, CD3 (surface or cytoplasmic) CD4, CD5, CD7,
and/or CD8. If the only T-cell markers present are CD4 and CD7, the
leukemia cells must also lack the myeloid markers CD33 and/or CD13.
2) T-ALL or T-LBL patients with relapsed/refractory disease. Patients with initial refractory disease should have received at least 2 multi-agent chemotherapy induction regimens. Patients in first or second relapse must have been refractory to at least 1 multi-agent chemotherapy reinduction regimen.
3) Have had at least 60 days between prior hematopoietic stem cell transplant and first dose of study drug.
4) Have a performance status of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) scale for adults.
5) Have adequate organ function: 1) hepatic: bilirubin </= 1.5 × the upper limit of normal (ULN) and ALT and AST </=3 × ULN. For patients with liver involvement, ALT and AST </=5 × ULN; 2) renal: calculated creatinine clearance >/=45 mL/min or a serum creatinine based on age/gender/
6) 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.
7) 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.
8) Have an estimated life expectancy of at least 2 months and in the judgment of the investigator, will be able to complete at least 2 cycles of treatment.
9) Have given written informed consent/assent prior to any study-specific procedures.All patients and/or their parents or legally authorized representatives must sign a written ICF. Assent, when appropriate, will be obtained according to institutional guidelines.
10) Are able to swallow capsules and tablets.
1) Are currently enrolled in a clinical trial involving an
investigational product or non approved use of a drug or device (other
than the study drug/device used in this study), or concurrently enrolled
in any other type of medical research judged not to be scientifically or
medically compatible with this study.
2) Have discontinued prior anticancer therapy less than 2 weeks prior to starting therapy or 5 half-lives (whichever is longer) with the following exceptions: 1) glucocorticoids administered as antileukemic treatment should be discontinued at least 5 days prior to starting therapy; 2) mercaptopurine may be dosed up to 5 days prior to first dose of LY3039478; 3) Vinca alkaloids may be dosed up to 7 days prior to first dose of LY3039478; 4)intrathecal chemotherapy may be dosed up to 7 days prior to first dose of LY3039478; 5) At the discretion of the investigator, hormone-sensitive prostate cancer patients who are in remission and stable on gonadotropin-releasing hormone (GnRH) agonist therapy and breast cancer patients who are stable on antiestrogen therapy (for example, an aromatase inhibitor) may have that treatment continued while they are enrolled in this study.
3) Have previously completed or withdrawn from this study or any other study investigating LY3039478 or other Notch inhibitors. (This exclusion criterion does not apply to patients who are re-screened prior to enrollment/randomization.)
4) Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol.
5) Have evidence of uncontrolled, active infection <7 days prior to administration of study medication.
6) Have current or recent (within 3 months of study drug administration) GI disease with chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease. Non chronic conditions (eg, infectious diarrhea) that are completely resolved for at least 1 week prior to starting study treatment are not exclusionary.
7) Have conditions requiring chronic systemic (not inhaled) glucocorticoid use, such as autoimmune disease or severe asthma. Low doses of corticosteroids are permitted.
8) Have active (symptomatic or requiring current medical treatment) graft versus host disease.
9) Have active leukemic involvement of the CNS as shown by spinal fluid cytology or imaging. A lumbar puncture is not required unless CNS involvement is clinically suspected. Patients with signs or symptoms of leukemic meningitis or a history of leukemic meningitis must have a blast-free cerebrospinal fluid within 14 days of the first day of study treatment.
10) Have a second primary malignancy or prior malignancy that, in the judgment of the investigator and following consultation with Lilly, may affect the interpretation of results. Patients with carcinoma in situ of any origin and patients with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the Lilly clinical research physician (CRP), are eligible for this study. The Lilly CRP will approve enrollment of patients with prior malignancies in remission before these patients are enrolled.
Information and next steps
Phase I/Phase II
For general questions about clinical trials: