The primary objective of this study is to compare the overall survival (OS) distributions between LY2157299 monohydrate plus lomustine therapy with lomustine plus placebo therapy (control arm), in patients who have relapsed or have progressive GB…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To compare the overall survival (OS) distributions between LY2157299 plus
lomustine therapy and lomustine plus placebo therapy (control arm) in patients
who have relapsed or have progressive GB after first-line treatment with
chemoradiation.
Secondary outcome
The secondary objectives of the study are:
- Pharmacokinetic (PK)
• To determine the population PK of LY2157299 monohydrate.
- Safety
• To provide additional safety information on LY2157299 monotherapy and
LY2157299 plus lomustine therapy and to evaluate the safety of LY2157299
monohydrate monotherapy and LY2157299 monohydrate plus lomustine therapy
relative to lomustine plus placebo therapy.
Pharmacodynamic (PD) - prognostic and predictive marker assessment
• To investigate in tumor tissue, biomarkers associated with tumor growth and
the TGF-* signaling pathway (phosphorylated SMAD [pSMAD] and other TGF-β-
related biomarkers, O6-methylguanine-DNA methyltransferase [MGMT] promoter
status, and other relevant tumor genetic information [eg, isocitrate
dehydrogenase (IDH1) mutation]) and its association with clinical responses.
• To determine serum/plasma tumor markers and secreted proteins (eg, S100β,
lactate dehydrogenase [LDH], TGF-β, and PF4) and their association with
clinical responses.
• To determine T cell biomarker responses, including T regulatory cell counts
(eg, CD4+CD25+FoxP3+ T cells) and their association with clinical responses.
- Efficacy
• To estimate the OS and hazard ratio (HR) between lomustine plus placebo
therapy and LY2157299 monohydrate monotherapy and between LY2157299 monohydrate
plus lomustine therapy and LY2157299 monohydrate monotherapy.
• To estimate progression-free survival (PFS) distributions for each treatment
arm and estimate additional parameters from both the OS distributions and PFS
distributions for each treatment arm (such as median OS and PFS, OS and PFS
rates at 6 months).
• To estimate tumor response rate based on Response Assessment in
Neuro-Oncology (RANO) criteria for each treatment arm.
- Health Outcomes
• To assess patient-reported symptoms using the MD Anderson Symptom
Inventory-Brain Tumor (MDASI-BT) and assess neurocognitive function using the
Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Parts A and B,
and Controlled Oral Word Association (COWA) for each treatment arm.
Background summary
Transforming growth factor beta (TGF-β) is an important protein that regulates
immune response to and metastatic spread of tumor cells. It is also an
important regulator of neoangiogenesis.
LY2157299 monohydrate is a small molecule designed to selectively inhibit the
serine/threonine kinase of the TGF-β receptor type I (TGF-βRI). Thus, the
antitumor effect of LY2157299 monohydrate is expected to result in an increased
tumor immune surveillance, reduced metastatic spread, and decreased
tumor-associated neoangiogenesis.
In glioblastoma (GB), anaplastic astrocytomas, anaplastic oligoastrocytoma, or
anaplastic oligodendroglioma, LY2157299 monohydrate is expected to reduce
neoangiogenesis, enhance antitumor cytotoxic T cells, and reduce fibrogenic
remodeling associated with tumor necrosis, radiation, and surgery.
In a recent first-human-dose study, H9H-MC-JBAH (Study JBAH), single-agent
administration of LY2157299 monohydrate has been associated with 2 complete and
3 partial tumor responses in 39 patients with relapsed and recurrent GB.
Combination with lomustine and LY2157299 monohydrate was safe at the 160-mg/day
and 300-mg/day doses. Preliminary information indicated 2 partial responses in
26 patients who were treated with the combination of lomustine and LY2157299
monohydrate.
This clinical activity of LY2157299 monohydrate together with the scientific
hypothesis that blocking the TGF-β signaling pathway in GB will have clinical
benefit provide the justification to conduct a trial with LY2157299 monohydrate
in patients who relapsed after first-line treatment for GB.
Study objective
The primary objective of this study is to compare the overall survival (OS)
distributions between LY2157299 monohydrate plus lomustine therapy with
lomustine plus placebo therapy (control arm), in patients who have relapsed or
have progressive GB after first-line treatment with chemoradiation.
The secondary objectives of the study are:
- Pharmacokinetic (PK)
• To determine the population PK of LY2157299 monohydrate.
- Safety
• To provide additional safety information on LY2157299 monotherapy and
LY2157299 plus lomustine therapy and to evaluate the safety of LY2157299
monohydrate monotherapy and LY2157299 monohydrate plus lomustine therapy
relative to lomustine plus placebo therapy.
Pharmacodynamic (PD) - prognostic and predictive marker assessment
• To investigate in tumor tissue, biomarkers associated with tumor growth and
the TGF-* signaling pathway (phosphorylated SMAD [pSMAD] and other TGF-β-
related biomarkers, O6-methylguanine-DNA methyltransferase [MGMT] promoter
status, and other relevant tumor genetic information [eg, isocitrate
dehydrogenase (IDH1) mutation]) and its association with clinical responses.
• To determine serum/plasma tumor markers and secreted proteins (eg, S100β,
lactate dehydrogenase [LDH], TGF-β, and PF4) and their association with
clinical responses.
• To determine T cell biomarker responses, including T regulatory cell counts
(eg, CD4+CD25+FoxP3+ T cells) and their association with clinical responses.
- Efficacy
• To estimate the OS and hazard ratio (HR) between lomustine plus placebo
therapy and LY2157299 monohydrate monotherapy and between LY2157299 monohydrate
plus lomustine therapy and LY2157299 monohydrate monotherapy.
• To estimate progression-free survival (PFS) distributions for each treatment
arm and estimate additional parameters from both the OS distributions and PFS
distributions for each treatment arm (such as median OS and PFS, OS and PFS
rates at 6 months).
• To estimate tumor response rate based on Response Assessment in
Neuro-Oncology (RANO) criteria for each treatment arm.
- Health Outcomes
• To assess patient-reported symptoms using the MD Anderson Symptom
Inventory-Brain Tumor (MDASI-BT) and assess neurocognitive function using the
Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Parts A and B,
and Controlled Oral Word Association (COWA) for each treatment arm.
Study design
This is a 3-arm, randomized (1:2:1), multicenter, global, Phase 2 study of
LY2157299 monohydrate monotherapy or LY2157299 monohydrate plus lomustine
therapy compared to lomustine plus placebo therapy in patients with relapsed
GB. In contrast to the LY2157299 monohydrate monotherapy arm, patients and
investigators will be blinded to the LY2157299 monohydrate or placebo
assignment in either the LY2157299 plus lomustine or the lomustine plus placebo
therapy arms.
Intervention
Patients who meet all criteria for enrollment will be randomly assigned in a
1:2:1 ratio to receive:
- LY2157299 monotherapy
- LY2157299 plus lomustine therapy
- Lomustine plus placebo therapy
LY2157299 monohydrate, 300 mg/day, given orally for 14 days followed by 14 days
of rest, for a 28-day cycle.
LY2157299 monohydrate-matched placebo, given orally for 14 days, followed by 14
days of rest, for a 28-day cycle.
Lomustine will be given orally once every 6 weeks. The first lomustine dose
will be 100 mg/m2, and all following doses can be escalated to a maximum of 130
mg/m2, at the investigator*s discretion.
Study burden and risks
Risks associated with LY2157299
Monohydrate:
The most common risks and discomforts reported by patients who received
LY2157299 monohydrate monotherapy are weakness and nausea. Other risks and
discomforts reported by people who have received LY2157299 monohydrate
monotherapy include low levels of cells that prevent bleeding, inflammation at
the anus, loose stool, dry mouth, cramping, bloating, stomach tenderness,
incontinence, gas, gastritis, mucous in stools, tiredness, stroke, numbness in
the fingers, vomiting, dizziness, shortness of breath, increased bilirubin in
blood, blood clot in the lung, and protein in the urine. Of these, 4 people
had effects that were serious enough to require hospitalization.
Risks associated with Lomustine:
• allergic reactions like skin rash, itching or hives, swelling of the face,
lips, or tongue
• low blood counts - this medicine may decrease the number of white blood
cells, red blood cells and platelets. You may be at increased risk for
infections and bleeding.
• signs of infection - fever or chills, cough, sore throat, pain or difficulty
passing urine
• signs of decreased platelets or bleeding - bruising, pinpoint red spots on
the skin, black, tarry stools, blood in the urine
• signs of decreased red blood cells - unusually weak or tired, fainting
spells, lightheadedness
• breathing problems
• changes in vision
• confusion
• dry cough
• mouth sores
• swelling of the ankles, feet, hands
• trouble passing urine or change in the amount of urine
• unusual bleeding or bruising
• yellowing of the eyes or skin
Other side effects includes the following: hair loss, loss of appetite, nausea,
vomiting
Furthermore patients might experience discomforts during the study procedures:
Blood sampling, providing urine,
Echocardiogram, Magnetic Resonance Imaging (MRI), CT scan, contrasts for MRI
and CT
scans. Please refer to Appendix 2 of the Patient Information Sheets for more
information regarding the possible discomforts of these procedures.
Lilly Corporate Center N/A
IN 46285 Indianapolis
US
Lilly Corporate Center N/A
IN 46285 Indianapolis
US
Listed location countries
Age
Inclusion criteria
Eligible male and female patients are required to: (1) have confirmed diagnosis of relapsed intracranial or secondary blioblastoma, 2) evidence of tumor progression , 3) may have undergone prior surgical resection and will be eligible if patients have recovered from the effects of surgery and evaluable or measurable disease is present , 4) have available tumor tissue, 5)have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, 6) Have discontinued all previous treatments for cancer excluding palliative treatments and recovered from the acute effects of therapy , 7) Have adequate organ function,8)Are males or females at least 18 years old at the time of screening: Females must be women of child-bearing potential who test negative for pregnancy (at the time of enrollment) or postmenopausal women - Males must agree to use a reliable method of birth control (during the study and for at least 12 weeks following last dose of study drug), 8) Have given written informed consent/assent prior to any study-specific procedures, 9) Are able to swallow capsules (lomustine) and tablets (LY2157299/placebo).
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled;1) Are currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an investigational product (including vascular endothelial growth factor receptor [VEGF-R] inhibitors) 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 previously completed or withdrawn from this study or any other study investigating LY2157299.
3) Have moderate or severe cardiac disease
4) Received prior nitrosourea (including lomustine or Gliadel®/local carmustine) therapy.
5) Received prior bevacizumab as part of a first-line treatment for GB (unless the treatment was concluded 12 months prior to enrollment)
6) Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the patient*s ability to adhere to the protocol.
7) Have current acute or chronic myelogenous leukemia
8) Have a second primary malignancy that, in the judgment of the investigator and sponsor, may affect the interpretation of results
9) Are pregnant or breast-feeding women
10) Are unwilling or unable to participate in the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004418-40-NL |
| CCMO | NL39459.078.12 |