A Phase 1/2A Study of LAM561 in Adult Patients With Advanced Solid Tumours

Study Overview
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Brief Summary
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This is a phase 1/2A, open label, non-randomized study in patients with advanced solid tumours including malignant glioma

Detailed Description
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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

Official Title
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A Phase 1/2A Dose Escalation Study of LAM561 in Adult Patients With Advanced Solid Tumours Including Malignant Glioma

Conditions
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Glioma, Other Solid Tumours

Intervention / Treatment
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* Drug: LAM561


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Cohort 1<br>Intervention: LAM561. 7 dose cohorts of up to 6 patients have been performed in the dose escalation phase. The starting dose cohort received 250 mg twice daily. | Drug: LAM561<br>* 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.<br>|
| Experimental: Dose Cohort 2<br>Intervention: LAM561. 500 mg twice daily | Drug: LAM561<br>* 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.<br>|
| Experimental: Dose Cohort 3<br>Intervention: LAM561. 1g twice daily | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561 Dose Cohort 4<br>Intervention: LAM561. 2g twice daily | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561 Dose Cohort 5<br>Intervention: LAM561. 4g twice daily | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561Dose Cohort 6<br>Intervention: LAM561. 4g three times daily | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561 Dose Cohort 7<br>Intervention: LAM561. 8g twice daily | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561 Dose Expansion cohort. Glioma<br>Intervention: LAM561 at the MTD: 4g three times daily. Up to 10 patients with malignant glioma. | Drug: LAM561<br>* 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.<br>|
| Experimental: LAM561 Dose Expansion cohort. Non-glioma<br>Intervention: LAM561 at the MTD: 4g three times daily. Up to 10 patients with other advanced solid tumours that are suitable for biopsy. | Drug: LAM561<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events | All adverse events will be recorded including clinically significant physical examinations and vital signs, laboratory safety tests and 12-lead electrocardiograms | From the first dose of study drug until 30 days after the last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of LAM561 in blood measured by LC-MS/MS | Full profiles on Day 1 and Day 21 (dose escalation phase only), trough measurements on Day 8, 15 and 21 | 21 days | 
| Concentration of biomarkers in blood or tumour tissue | Effect on glial fibrillary acidic protein in glioma patients and effect on sphingomyelin and dihydrofolate reductase in patients with other solid tumours | 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) | 
| Concentration of micro RNA in blood | Blood samples for future analysis of micro RNA | 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) | 
| Radiological disease progression | 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). | Every 6 weeks until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion) | 
| Clinical disease progression |  | until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another general discontinuation criterion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioma, Solid Tumours, LAM561