A study evaluating the Safety and Efficacy of Entospletinib (GS-9973) in combination with standard of care in adult subjects with Relapsed or Refractory Acute Lymphoid Leukemia (ALL).

• Register: EUCTR
• Last refreshed on: 11 April 2016
• Main ID: EUCTR2015-002768-18-DE
• Date of registration: 01/02/2016
• Prospective Registration: Yes
• Primary sponsor: Gilead Sciences, Inc.
• Public title: A study evaluating the Safety and Efficacy of Entospletinib (GS-9973) in combination with standard of care in adult subjects with Relapsed or Refractory Acute Lymphoid Leukemia (ALL).
• Scientific title: A Phase 1b, Open-Label, Dose Escalation and Expansion Study Evaluating the Safety and Efficacy of Entospletinib (GS-9973) with Vincristine and Dexamethasone in Adult Subjects with Relapsed or Refractory Acute Lymphoid Leukemia (ALL)
• Date of first enrolment: 18/03/2016
• Target sample size: 35
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002768-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 0

Countries of recruitment

Canada, Germany, United States

Contacts

• Name: Clinical Trials Mailbox
• Affiliation: Gilead Sciences International Ltd

• Name: Clinical Trials Mailbox
• Affiliation: Gilead Sciences International Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1) =18 years of age
2) Previously treated ALL including Philadelphia chromosome (BCR-Abl) positive ALL who meet all of the following criteria:
a) Diagnosis of precursor B-cell ALL based on flow cytometry and histology
b) Previously treated subjects with primary refractory disease OR after first or subsequent relapse
c) Subjects with >10% lymphoblasts
d) Patients with Ph+ ALL must have failed treatment with at least one 2nd generation (ex. dasatanib) or 3rd generation (ex. ponatinib) tyrosine kinase inhibitor
3) Eastern Cooperative Oncology Group (ECOG) performance status = 2
4) Adequate organ function defined by the screening laboratory inclusion values and absence of known cardiac dysfunction
5) Required screening laboratory data (within 7 days prior to administration of GS-9973)
6) Discontinuation of all therapy (including radiotherapy, chemotherapy, tyrosine-kinase inhibitors [TKIs], immunotherapy, or investigational therapy) for the treatment of cancer as follows:
a) At least 1 week or 5 half-lives (whichever is longer) from the last dose of prior anti-cancer therapy and the initiation of study therapy
b) Exceptions or modifications to the above are as follows:
Medications that are typically part of a maintenance therapy for ALL, such as glucocorticoids or mercaptopurine, may be administered up to 3 days prior to the first dose, except vinca alkaloids which must be discontinued at least 14 Days prior to the start of study treatment. TKIs are not permitted to be continued at screening (eg, Gleevec). Subjects may receive hydroxyurea or apheresis if indicated for rapidly rising white blood cell count
c) CNS prophylaxis at least one week prior to first dose of GS-9973
d) For biologics (eg, monoclonal antibodies), washout period of 1 month beyond the recommended dosing interval and at least 4 weeks or 5 half-lives (whichever is longer) since the last dose
e) If prior stem cell transplant, subject must be at least 100 days from stem cell infusion and off all systemic anti-graft versus host disease (GVHD) medications
7) All acute toxic effects of any prior antitumor therapy must be resolved to Grade = 1 before enrolment, with the exception of alopecia (any grade permitted), or bone marrow parameters (any grades permitted)
8) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol recommended method of contraception from the screening visit (Visit 1) throughout the study treatment period and to 30 days from the last dose of GS-9973. A negative serum pregnancy test is required for female subjects at screening. Lactating females must agree to discontinue nursing before GS-9973 is administered.
9) For male subjects having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the start of GS-9973 throughout the study treatment period and for 90 days following the last dose of GS-9973. Also, male subjects should refrain from sperm
donation from the start of the GS-9973 throughout the study treatment period and for 3 months following the last dose of GS-9973.
10) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status,
Exclusion criteria:
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Diagnosis of mature B-cell ALL (Burkitt’s leukemia), or lymphoid blast crisis of chronic myelogenous leukemia (CML)
2) A life threatening illness, medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety or interfere with the absorption or metabolism of GS-9973
3) Subjects who are in first relapse and are > 18 months from initial establishment of CR at the time of relapse (late relapse)
4) Extramedullary involvement of ALL as the only site of disease (in the absence of evaluable marrow disease)
5) Active or symptomatic central nervous system (CNS) disease
For study purposes a subject will NOT be considered as having active CNS disease if the subject has documentation of prior CNS disease and has received treatment (IT or radiation) and are:
a) asymptomatic for the last 28 days prior to screening, and
b) has documented at least 2 negative cerebrospinal fluid (CSF) cytology (which must include 1 lumbar puncture [LP] within the study screening window)
6) Uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements. Subjects with active infection are permitted to enroll provided that the infection is documented to be under control and after discussion with medical monitor
7) History of myelodysplastic syndrome or solid organ transplantation
8) History of a non-lymphoid malignancy except for the following:
adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for > 1 year prior to the start of GS-9973, or any other cancer that has been in complete remission without treatment for = 5 years prior to enrolment
9) Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for GS-9973
10) Evidence of uncontrolled systemic bacterial, fungal, or viral infection at the start of GS-9973
11) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), HIV, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
12) Prior allogeneic bone marrow progenitor cell transplant within 100 days or on active systemic immunosuppression for graft versus host disease (GVHD) treatment or prophylaxis within 28 days prior to enrolment
13) Active (symptomatic or requiring current medical treatment within 28 days prior to the start of study treatment) for GVHD
14) Ongoing immunosuppressive therapy other than corticosteroids (corticosteroids being used for GVHD treatment are not permitted)
15) Current therapy with proton pump inhibitors (PPI) (as there is the potential to interfere with GS-9973 absorption)
16) Ongoing or recent treatment with an excluded medication
17) Pregnancy or breastfeeding
18) Ongoing active pneumonitis
19) Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 28 days prior to start of GS-9973 administration


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

Relapsed or Refractory Acute Lymphoid Leukemia (ALL)

Intervention(s)

Product Code: GS-9973
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Entospletinib
Other descriptive name: ENTOSPLETINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Code: GS-9973
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Entospletinib
Other descriptive name: ENTOSPLETINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: To determine the recommended dose of GS-9973 in combination with VCR and dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage ALL

To evaluate the therapeutic response of GS-9973 in combination with VCR and dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage ALL

Timepoint(s) of evaluation of this end point: Clinical/Laboratory tests will be carried out and AE will be recorded on Day 1 of lead in phase, Day 1/8/15/22/28 of Cycle 1 for DLT assessment. Afterwards safety will be assessed on the following time points: Day 1/8/15/22/28 of Cycle 2 and maintenance Cycle 1, on end of treatment visit and 30 day follow-up. Starting from maintenance Cycle 2, Day 1 is required and Day 8/15/22/28 visits are per the Investigator's discretion. One cycle = 28 days (4weeks).

Main Objective: To evaluate safety of entospletinib (GS-9973) in combination with vincristine (VCR) and dexamethasone in adult subjects with previously treated relapsed or refractory B-cell lineage ALL

Primary end point(s): The primary endpoint is safety. Safety will be evaluated by:
Occurrence of adverse events and laboratory abnormalities defined as dose limiting toxicities (DLTs)

Secondary Outcome(s)

Secondary end point(s): Overall Remission (CR or CRi) rate at end of induction - defined as the proportion of subjects who achieve a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) at end of induction
- Complete remission (CR) rate at end of induction
- Number and proportion of subjects who receive post-treatment HSCT
- Number and proportion of subjects who receive other post-treatment leukemia therapy
- Partial response (PR) rate at end of induction - defined as the proportion of subjects who achieve a partial response of marrow
- Overall Response (CR, CRi, or PR) rate at end of induction - defined as the proportion of subjects who achieve a complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or partial response (PR) at end of induction

Timepoint(s) of evaluation of this end point: Clinical/Laboratory tests will be carried out and AE will be recorded on Day 1 of lead in phase, Day 1/8/15/22/28 of Cycle 1 for DLT assessment. Afterwards safety will be assessed on the following time points: Day 1/8/15/22/28 of Cycle 2 and maintenance Cycle 1, on end of treatment visit and 30 day follow-up. Starting from maintenance Cycle 2, Day 1 is required and Day 8/15/22/28 visits are per the Investigator's discretion. One cycle = 28 days (4weeks). Bone marrow aspirate/biopsy will be carried out on Day 8/28 of Cycle 1, Day 28 of Cycle 2 and the end of study treatment visit, Bone marrow evaluations can be performed as clinically indicated per institutional standards in the maintenance cycles.

Secondary ID(s)

GS-US-339-1560

Source(s) of Monetary Support

Gilead Sciences, Inc