LAM561 With RT and TMZ for Adults With Glioblastoma
- Conditions
- Primary GlioblastomaGlioblastoma Multiforme
- Interventions
- Registration Number
- NCT04250922
- Lead Sponsor
- Laminar Pharmaceuticals
- Brief Summary
The proposed Phase IIB/III randomized, double-blind, placebo-controlled trial in subjects with newly diagnosed primary glioblastoma multiforme (ndGBM) aims to compare the efficacy and safety of LAM561 versus placebo, given with standard of care (SoC) therapy of radiation therapy plus temozolomide (TMZ), followed by an adjuvant treatment of 6 month period of TMZ and then LAM561 or placebo in monotherapy.
- Detailed Description
This is a randomized, double-blind, placebo-controlled, 2 parallel arms (1:1 ratio), adjuvant trial to assess the efficacy of LAM561 versus placebo in patients with newly diagnosed, IDH1 wildtype, GBM. In all arms, patients will receive the SoC and will be randomized to receive either placebo or LAM561 dose.
The study is planned to enrol 140 patients. The primary endpoints of the study are PFS (for CMA) and OS (for FMA) as assessed after observing at least 66 PFS events and at least 90 OS events, respectively. It is expected that the analysis for PFS will be performed 1-2 years earlier than the analysis for OS.
An IDMC (Independent Data Monitoring Committee) meeting took place to assess the trial's futility and safety data from the start of the trial until September 2023. The IDMC had open access to the data without blinding; after analysis IDMC concluded that there were no concerns that would necessitate stopping the study for ethical reasons or safety issues that could adversely affect patients due to taking the medication, so the study is continuing as normal with no changes.
After 45 events for PFS are observed, a formal interim analysis will be performed and the data reviewed by an Independent Data Monitoring Committee (IDMC) or may be activated by the IDMC 12 months after the inclusion of the last patient if follow up is sufficient to identify an overall PFS or OS significant deviation from the literature. After reviewing the interim results, the iDMC will make recommendations regarding: the sample size and the continuation of the trial overall.
Further, the sample size and events will be re-estimated to ensure that the statistical power is maintained given the estimated treatment effect at interim analysis. The events/sample size increase will be based on the considerations of the success probability.
For that purpose, based on the conditional power, the interim results will be classified into the following zones: favourable, unfavourable or promising.
If the interim results fall in the promising zone, then it is planned to increase the total number of events both for PFS and OS by up to 50%, with up to 99 events for PFS and up to 135 events for OS. The total sample size will also be increased to up to 210 patients to ensure the desired number of events within a realistic time. If the interim results are favourable or unfavourable, the study size will remain as initially planned with 66 events for PFS and 90 for OS, collected from 140 patients.
The IDMC committee experts met in February 2024 after 45 PFS events occurred in the trial. Unblinded medical and clinical statistical data from 103 patients were evaluated to assess the efficacy - progression free survival (tumour growth or clinical deterioration) - of LAM561. The IDMC confirmed that, at the current level of evidence, after evaluating the Conditional Power of the unblinded results, no futility has been identified and recommends continuation of the study without modification.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 140
Not provided
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Known hypersensitivity to any component of the investigational product.
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Any other investigational drug within the preceding 30 days. Prior, concomitant, or planned concomitant treatment with anti-neoplastic aim including (but not limited) to NovoTumor Treatment Fields (Novo TTF), bevacizumab, intratumoural or intracavitary anti-neoplastic therapy (e.g Gliadel wafers), or other experimental therapeutics intended to treat the tumour.
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Subjects who underwent "only biopsy" resection
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Anticancer therapy within 4 weeks of study entry (6 weeks for mitomycin and nitrosoureas)
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Other major surgery within the preceding 30 days
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Allergy, hypersensitivity or other intolerability to temozolomide and its excipients, patients with hypersensitivity to dacarbazine and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
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Unable to undergo MRI
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Presenting with diffuse midline gliomas or multifocal GBM (distant from the flare or contralateral) or rapid progression between early post-surgery MRI and pre-radiotherapy MRI
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Uncontrolled or significant cardiovascular disease
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A history of uncontrolled hyperlipidaemia and/or the need for concurrent lipid lowering therapy
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Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide, glyburide or nateglanide)
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Past medical history of uncontrolled clinically significant active or chronic gastrointestinal disorders (for example, Crohn's disease, celiac disease, untreated stomach ulcers, etc) and gastro-inflammatory pathologies
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Uncontrolled diabetes mellitus, with glycated haemoglobin (HbA1c) levels at the screening visit of ≥7.5%
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Cardiac disease, defined specifically as either
- Mean resting corrected QT interval (QTc) > 470 msec (for women) and > 450 ms (for men) obtained from 3 consecutive ECGs
- Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (example, complete left bundle branch block, third degree heart block)
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for Torsades de Pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age
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Previous malignancies within the last three years other than ndGBM, except successfully treated squamous cell carcinoma of the skin, superficial bladder cancer, and in situ carcinoma of the cervix.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B: SoC + 12 g/day of LAM561 RT Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over \~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm B will receive LAM561 every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance Phase will be scheduled \~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm B will receive LAM561 during the Maintenance Phase. Patients will continue to be administered with LAM561 after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment. Arm A: SoC + placebo for LAM561 RT Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over \~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm A will receive placebo every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance (Adjuvant) Phase will be scheduled \~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm A will receive placebo every day during the first 3 weeks of each 28-day cycle and until progression. Patients will continue with Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment. Arm B: SoC + 12 g/day of LAM561 LAM561 Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over \~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm B will receive LAM561 every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance Phase will be scheduled \~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm B will receive LAM561 during the Maintenance Phase. Patients will continue to be administered with LAM561 after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment. Arm A: SoC + placebo for LAM561 TMZ Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over \~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm A will receive placebo every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance (Adjuvant) Phase will be scheduled \~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm A will receive placebo every day during the first 3 weeks of each 28-day cycle and until progression. Patients will continue with Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment. Arm B: SoC + 12 g/day of LAM561 TMZ Chemoradiation Phase: all subjects undergo focal RT, with a treatment given 5 days per week over \~6 weeks (no more than 7 weeks). TMZ will be administered at 75 mg/m2 orally, once daily, continuously throughout the RT for a maximum of 49 days. Subjects in Arm B will receive LAM561 every day from Day 1 of week 3 to the end of this Phase. The start of the first cycle during the Maintenance Phase will be scheduled \~28 days (and never more than 42 days) after the last day of chemoradiation. During the Maintenance Phase, subjects will receive oral TMZ 150-200 mg/m2 once daily on Days 1-5 of each 28-day cycle for 6 cycles. Subjects in Arm B will receive LAM561 during the Maintenance Phase. Patients will continue to be administered with LAM561 after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression, unacceptable toxicity or refusal to continue study treatment.
- Primary Outcome Measures
Name Time Method To evaluate the efficacy of LAM561 in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ. Assessed after observing at least 90 OS events To evaluate the efficacy of LAM561 in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ, as assessed by
- Overall Survival (OS)
- Secondary Outcome Measures
Name Time Method To evaluate measures of clinical response Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria
To evaluate Health-related Quality of Life (HRQoL) Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression HRQoL assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC-QLQ C30, version 3.0 and brain cancer specific QLQ-BN20.
The EORTC QLQ-C30/BN20 as outlined in SoA. These assessments should be completed prior to study drug administration and any other study procedures being performed at these visits, and prior to discussing with the subject that their disease has progressed.To evaluate additional measures of efficacy Baseline and Post-baseline: day 1 of each odd cycle of maintenance/monotherapy phase and at progression Time to Progression (TTP) (as assessed using RANO criteria)
To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) parameters At week 3 and 5 (day in both cases) of chemo-radiotherapy phase and at day 1 and 15 of cycle 1 of the maintenance phase Blood samples for determination of plasma concentrations of LAM561 in combination with RT and/or TMZ.
Area Under the plasma concentration-time Curve (AUC)
Trial Locations
- Locations (22)
Hospital Clinic
🇪🇸Barcelona, Spain
Hospital Clínico San Carlos
🇪🇸Madrid, Spain
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
The Royal Marsden Hospital
🇬🇧London, United Kingdom
Cambridge university hospital
🇬🇧Cambridge, United Kingdom
Freeman Hospital's Northern Centre of Cancer Care
🇬🇧Newcastle, Newcastle Upon Tyne, United Kingdom
Institut universitaire du cancer
🇫🇷Toulouse, France
University of Turin
🇮🇹Turin, Italy
Gustave Roussy University Hospital
🇫🇷Rennes, France
Institut Cancerologie de L'Ouest (ICO)
🇫🇷Angers, France
Centre Eugène Marquis (CEM)
🇫🇷Rennes, France
Reaserch Fund of the Hadassah Medical Organization
🇮🇱Jerusalem, Israel
Istituto Nazionale Tumori "Regina Elena"
🇮🇹Roma, Italy
Istituto Nazionale Neurologico Carlo Besta
🇮🇹Milan, Italy
Hospital Universitario Reina Sofía
🇪🇸Córdoba, Andalucía, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Andalucía, Spain
University Hospitals Birmingham NHS Foundation Trust - New Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Hospital Universitari i Politécnic La Fe.
🇪🇸Valencia, Comunidad Valenciana, Spain
Hospital Universitario 12 De Octubre
🇪🇸Madrid, Spain
Hospital Parc Tauli
🇪🇸Sabadell, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Istituto Oncologico Veneto IRCCS
🇮🇹Padova, Veneto, Italy