Glioma, Other Solid Tumours
Conditions
Keywords
Glioma, Solid Tumours, LAM561
Brief summary
This is a phase 1/2A, open label, non-randomized study in patients with advanced solid tumours including malignant glioma
Detailed description
This is an open label, non-randomized study in patients with advanced solid tumours including malignant glioma. The study will be performed in two phases - a dose escalation phase following a standard 3+3 design to establish dose-limiting toxicity (DLT) and a safe dose of LAM561 followed by two expanded safety cohorts (approximately 10 of whom have malignant glioma and approximately 10 of whom have other advanced solid tumours that are suitable for biopsy) treated at the maximum tolerated dose (MTD). If the MTD is well tolerated in the expanded safety cohorts, that dose becomes the recommended phase 2 dose (RP2D). During each dose cohort, at least one week must elapse between the first and subsequent patients receiving treatment with LAM561. Patients may receive palliative localized radiotherapy, if needed (however, this lesion cannot be a target lesion for evaluation of the treatment response). Safety, pharmacokinetics (PK), pharmacodynamics and efficacy will be evaluated during the study at pre-defined timepoints
Interventions
DRUGLAM561
Patients will receive treatment cycles of 21 days, until any criterion for discontinuation (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion) is met. Patients are expected to receive between one and 6 cycles of treatment. The treatment period may be extended if clinical benefit is shown. In the event of significant GI toxicity, the treatment schedule may be modified from continuous dosing to an intermittent regime In the case of toxicity, the dose of LAM561 may be reduced or delayed by up to 14 days at the discretion of the Investigator. A maximum of two dose reductions will be permitted per patient. Treatment holidays of no more than 14 days are also permitted for reasons other than toxicity. Intra-patient dose escalation may be permitted in certain specific circumstances.
Sponsors
Specialized Medical Services (SMS)-Oncology BV
Royal Marsden NHS Foundation Trust
Northern Institute for Cancer Research, Newcastle
Vall d'Hebron Institute of Oncology
Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao
Onkologikoa, San Sebastián.
Laminar Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females providing written, informed consent * Histologically- or cytologically-confirmed advanced solid malignancy that is refractory to standard-of-care treatment, or for which there is no standard therapy. If this is glioma:Grade III / Grade IV malignant glioma recurring or progressing after first or second line standard-of-care treatment and true progressive disease, confirmed according to the RANO criteria 4. * Life-expectancy of at least 12 weeks * Eastern cooperative oncology group (ECOG) performance status of 0-2 * Safety laboratory tests and ECGs within specified limits. * Using adequate contraception, where applicable * Presence of lesions suitable for biopsy (mandatory for non-glioma patients enrolled in the expanded safety cohort and highly desirable for non-glioma patients enrolled in the dose escalation phase)
Exclusion criteria
* Anti cancer therapy within 4 weeks (6 weeks for mitomycin and nitrosureas and 2 weeks for palliative radiotherapy) * NCI Common terminology criteria for adverse events (CTCAE) \>Grade 1 toxicities from prior chemotherapy or radiotherapy that could impact on safety outcome assessment * Recent \>Grade 1 intracranial or intratumoural haemorrhage either by CT or MRI scan. Patients with resolving haemorrhage changes, punctuate haemorrhage or haemosiderin may enter the study * Significant or uncontrolled cardiovascular disease, unstable angina or myocardial infarction within the preceding 6 months * Known impairment of GI function that could alter the absorption of study drug * History of uncontrolled hyperlipidemia and/or the need for concurrent lipid lowering therapy * Concurrent severe and/or uncontrolled other medical disease that could compromise participation in the study * Taking warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide, glyburide or nateglanide) * Pregnant or breast feeding Other protocol specific criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with adverse events | From the first dose of study drug until 30 days after the last dose of study drug | All adverse events will be recorded including clinically significant physical examinations and vital signs, laboratory safety tests and 12-lead electrocardiograms |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of LAM561 in blood measured by LC-MS/MS | 21 days | Full profiles on Day 1 and Day 21 (dose escalation phase only), trough measurements on Day 8, 15 and 21 |
| Concentration of biomarkers in blood or tumour tissue | First 22 days then every 9 cycles until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion) | Effect on glial fibrillary acidic protein in glioma patients and effect on sphingomyelin and dihydrofolate reductase in patients with other solid tumours |
| Concentration of micro RNA in blood | First 22 days then every 9 cycles until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion) | Blood samples for future analysis of micro RNA |
| Radiological disease progression | Every 6 weeks until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion) | Measurement by CT or MRI scan. Changes scored according to Response Assessment in Neuro-oncology (RANO) criteria (for glioma patients) or Response evaluation criteria in solid tumours (RECIST v1.1) (for other solid tumour patients). |
| Clinical disease progression | until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion | — |
Countries
Spain, United Kingdom
Outcome results
None listed