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

NCT ID: NCT01792310

Last Updated: 2023-02-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-31
• Study Completion Date: 2016-09-30

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

Conditions

Glioma; Other Solid Tumours

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Cohort 1

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.

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

Dose Cohort 2

Intervention: LAM561. 500 mg twice daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

Dose Cohort 3

Intervention: LAM561.

1g twice daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561 Dose Cohort 4

Intervention: LAM561. 2g twice daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561 Dose Cohort 5

Intervention: LAM561. 4g twice daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561Dose Cohort 6

Intervention: LAM561. 4g three times daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561 Dose Cohort 7

Intervention: LAM561. 8g twice daily

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561 Dose Expansion cohort. Glioma

Intervention: LAM561 at the MTD: 4g three times daily. Up to 10 patients with malignant glioma.

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

LAM561 Dose Expansion cohort. Non-glioma

Intervention: LAM561 at the MTD: 4g three times daily. Up to 10 patients with other advanced solid tumours that are suitable for biopsy.

Group Type: EXPERIMENTAL

LAM561

Intervention Type: DRUG

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.

Interventions

LAM561

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.

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Specialized Medical Services (SMS)-Oncology BV

UNKNOWN

Sponsor Role: collaborator

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Northern Institute for Cancer Research, Newcastle

UNKNOWN

Sponsor Role: collaborator

Vall d'Hebron Institute of Oncology

OTHER

Sponsor Role: collaborator

Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao

UNKNOWN

Sponsor Role: collaborator

Onkologikoa, San Sebastián.

UNKNOWN

Sponsor Role: collaborator

Laminar Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Professor Johann de Bono, MB ChB FRCP MSc PhD

Role: STUDY_CHAIR

The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG

Prof. Ruth Plummer, BMBCh, MRCP, Cert Me

Role: PRINCIPAL_INVESTIGATOR

Northern Institute for Cancer Research, Newcastle

Dr Jordi Rodon

Role: PRINCIPAL_INVESTIGATOR

Vall d'Hebron Institute of Oncology

Dr Juanita Lopez

Role: PRINCIPAL_INVESTIGATOR

The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG

Dr Ricardo Fernandez Rodriguez

Role: PRINCIPAL_INVESTIGATOR

Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao

Dr Ander Urruticoechea Ribate

Role: PRINCIPAL_INVESTIGATOR

Onkologikoa, San Sebastián.

Locations

Vall D'Hebron Institute of Oncology

Barcelona, , Spain

Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre

Bilbao, , Spain

Onkologikoa

San Sebastián, , Spain

Sir Bobby Robson Cancer Trials Research Centre, The Northern Centre for Cancer Care, Freeman Hospital

Newcastle, Newcastle Upon Tyne, United Kingdom

The Royal Marsden Hospital Drug Development Unit

Sutton, Surrey, United Kingdom

Countries

Spain; United Kingdom

References

Lopez J, Lai-Kwon J, Molife R, Welsh L, Tunariu N, Roda D, Fernandez-Garcia P, Llado V, McNicholl AG, Rossello CA, Taylor RJ, Azaro A, Rodon J, Sludden J, Veal GJ, Plummer R, Urruticoechea A, Lahuerta A, Mujika K, Escriba PV. A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma. Br J Cancer. 2023 Sep;129(5):811-818. doi: 10.1038/s41416-023-02356-1. Epub 2023 Jul 24.

Reference Type: DERIVED

PMID: 37488446 (View on PubMed)

Other Identifiers

EudraCT 2012-001527-13

Identifier Type: REGISTRY

Identifier Source: secondary_id

MIN-001-1203

Identifier Type: -

Identifier Source: org_study_id