Neoplasms

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Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

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.

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.

Subjects in Arm B will receive orally LAM561 during the Chemoradiation Phase.

Subjects in Arm B will receive LAM561 orally during the Maintenance (Adjuvant) Phase. Patients will continue to be administered with LAM561/Placebo after cycle 6 of the monotherapy phase until end of study. Adjuvant treatment will be discontinued upon determination of tumour progression as defined by RANO criteria, unacceptable toxicity, or refusal to continue study treatment.

LAM561

TMZ will be administered at 75 mg/m2, orally, once daily, continuously from Day 1 of radiotherapy to the last day of radiation for a maximum of 49 days.

During the Maintenance (Adjuvant) Phase, all subjects will receive oral TMZ 150 - 200 mg/m2 once daily on Days 1 - 5 of each 28-day cycle for 6 cycles.

During the Chemoradiation Phase, all subjects will undergo focal RT, with one treatment given daily 5 days per week over approximately 6 weeks (and no more than 7 weeks).

Adrian Gerald McNicholl

Elodie Vauleon, Dr.

Frederic Dhermain, Dr.

Elizabeth Cohen-Jonathan Moyal, Dr.

Giuseppe Lombardi, Dr.

Francesco DiMeco Dr.

Veronica Villani, Dr.

Riccardo Soffietti Dr.

Sonia García, Dr.

Miriam Alonso, Dr.

Regina Gironés Dr.

Estela Pineda, Dr.

Maria Martinez Dr.

Maria Vieito, Dr.

Pedro Pérez Segura, Dr.

Juan Manuel Sepulveda-Sanchez, Dr.

Júlia Giner, Dr.

Joanne Lewis, Dr.

Helen Benghiat, Dr.

Harris Fiona, Dr.

Liam Welsh, Dr.

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.

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.

This is a randomized, double-blind, placebo-controlled, 2 parallel arms (1:1), adjuvant trial to assess the efficacy of LAM561 vs placebo in patients with ndGBM. The 2 arms are: Arm A: SoC + placebo for LAM561; Arm B: SoC + 12g/day of LAM561

Treatment consists of 3 phases:

1. Chemoradiotherapy (6 to 7 weeks)

   * RT in daily fractions of 2Gy, 5 days per week (60Gy)
   * TMZ 75mg/m2 daily (maximum of 49 days)
   * Placebo or LAM561 for 4 weeks (from week 3 to week 6, both inclusive) -Washout period (4 weeks)
2. Maintenance (4-week cycles, maximum of 6 cycles)

   * Placebo/LAM561 daily in the first 3 weeks of each cycle, followed by 7 days washout
   * TMZ 150-200mg/m2 daily in the first 5 days of each cycle
3. Monotherapy: 4-week cycles until disease progression, unacceptable toxicity or lack of clinical benefit Placebo/LAM561 daily in the first 3 weeks of each cycle followed by 7 days washout

At the Screening Visit, the IRT will assign a unique number to the subject. The site will use the IRT to receive drug kit numbers and a unique randomization number.

Subjects will be randomized to Arm A or B in a 1:1 ratio. Drug kit numbers and treatment content will be assigned according to a list generated before the start of the study. At interim, the IRT vendor will transfer the list of attribution to the iSCs. After the final lock, the list of attribution will be transmitted to the company involved in analysis. The IRT vendor will be in charge of the stock management/logistics in each site and shipments. Upon receipt of study drug, the study site will acknowledge receipt in the IRT system.

The investigators, the study site personnel and subject will remain blinded to throughout the course of the study. The IRT will provide access to for a subject in case of medical emergency. If sponsor/clinical team should break the blind, the reason will be documented on the eCRF.

LAM561 With RT and TMZ for Adults With Glioblastoma

A Randomized, Double-blind, Placebo-controlled Adjuvant Trial in Newly Diagnosed Primary Glioblastoma Subjects to Assess the Efficacy and Safety of LAM561 in Combination With Radiotherapy and Temozolomide Standard of Care Treatment.

To evaluate the efficacy of LAM561 in combination with the standard of care (SoC) treatment of radiotherapy (RT) and TMZ, as assessed by

- Progression Free Survival (PFS) using the Response Assessment in Neuro-Oncology (RANO) criteria

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)

Changes in neurological function, based on Neurologic Assessment in Neuro-Oncology (NANO) criteria

Time to Progression (TTP) (as assessed using RANO criteria)

Blood samples for determination of plasma concentrations of LAM561 in combination with RT and/or TMZ.

Maximum Plasma Concentration \[Cmax\]

Blood samples for determination of plasma concentrations of LAM561 in combination with RT and/or TMZ.

Lowest plasma concentration reached before the next dose is administered (Trough)

Blood samples for determination of plasma concentrations of LAM561 in combination with RT and/or TMZ.

Area Under the plasma concentration-time Curve (AUC)

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 QLQ-C30 is a 30-item patient self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/HRQoL scale, and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much". The QLQ-C30 was developed and validated for use in a cancer patient population, and its reliability and validity is highly consistent across different language-cultural groups.

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 QLQ-BN20 is a 20-item patient self-report questionnaire that was developed specifically as a module for subjects with brain cancer. It consists of four domain scores, including future uncertainty, visual disorder, motor dysfunction, and communication deficit, as well as seven individual symptom items (headache, seizures, drowsiness, hair loss, itching, difficulty with bladder control, and weakness of both legs). Subjects rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A retrospective validation study has been conducted confirming its psychometric validity.

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.

Laboratory Corporation of America

Northern Institute for Cancer Research, Newcastle

Theradis pharma

LIPODOM THERAPEUTICS

Laminar Pharmaceuticals

Vaccines

Autologous dendritic cells loaded with autologous tumor antigens cryopreserved in CryoStor 5, and admixed 500 mcg GM-CSF diluted in saline

Autologous monocytes cryopreserved in CryoStor 5, and admixed 500 mcg GM-CSF diluted in saline

Therapeutic autologous dendritic cell vaccine

AV-GBM-1

Autologous monocytes

Jim Langford

Robert O Dillman, MD

This is a multi-center, double-blind, 2:1 randomized phase III trial to determine whether the addition of AV-GBM-1, a therapeutic, patient-specific dendritic cell vaccine, to standard therapy increases OS of patients with a recent diagnosis of primary GBM.

The intent is to enroll approximately 726 patients for tumor collection to enroll 690 who are eligible for treatment at the time of randomization and who have granted consent for participation. Because of the lack of toxicity, there are no restrictions related to performance status or blood tests at the time of treatment. The key endpoint is OS from date of first injection after RT/TMZ; secondary endpoints are PFS from date of first injection, and OS and PFS from date of randomization prior to RT/TMZ. Date of PFS will be determined by the principal investigator at each site.

This is a multi-center, double-blind, 2:1 randomized phase 3 trial to determine whether the addition of AV-GBM-1 to standard therapy increases OS of patients with a recent diagnosis of primary GBM.

Patients will sign two treatment-related consents, one for obtaining fresh tumor tissue at the time of craniotomy for the purpose of establishing a short-term tumor cell line and for awareness of subsequent leukapheresis procedure, and the other for randomization and participation in the randomized trial. As required for related medical procedures, patients will sign medical consents for craniotomy/tumor resection, and for leukapheresis to obtain monocytes for the MC control arm, or to manufacture DC.

Key eligibility criteria are (1) recovered from maximal safe surgical resection surgery from which a short-term cell culture has been established, (2) undergone leukapheresis prior to planned concurrent RT/TMZ, from which a sufficient number of MC have been derived, (3) screened, stratified and randomized prior to starting RT/TMZ. Patients will be stratified by age (70 years or greater or less than 70), KPS (90 or 100 vs 70 or 80), MGMT promotor-methylation (yes or no), and IDH-mutation status (mutated or wild-type), then randomized 2:1 (AV-GBM-1 vs MC control).

The final products will be manufactured while the patient is being treated with RT/TMZ. After recovery from RT/TMZ, one of the study agents, either the DC-ATA AV-GBM-1 or autologous MC control, will be administered weekly for three weeks just prior to starting adjuvant TMZ, and then every four weeks concurrently with, adjuvant TMZ or second-line therapy per managing physician. Both products are admixed with adjuvant 500 mcg of GM-CSF by a local pharmacist, just prior to each injection. The pharmacist, the patient, their health care givers and local research team will be masked as to whether the patient is receiving AV-GBM-1 or MC control, which are similar in appearance. Only the AIVITA manufacturing team will be aware of randomization so that the appropriate product can be manufactured per SOPs.

The first 3 weekly SC injections of study agent will be administered prior to beginning adjuvant or salvage temozolomide, temozolomide plus bevacizumab, or temozolomide plus tumor treating fields. Thereafter study agents will be injected about every 28 days for up to 18 additional vaccines (i.e. a total of 21 vaccines over 18 months from the start of investigational therapy. Depending on the number of study-agent doses available, additional leukaphereses and manufacturing of more study agent may be required if treatment is to continue up to 18 months from the start of therapy. In previous trials, 8 total injections were given over 6 months. In this trial up to 21 doses may be given over 18 months.

In previous trials each patient-specific batch of DC-ATA was divided into 10 aliquots, 8 of which were intended for injection. The range of cells was from 1 to over 30 million per aliquot. However, the clinical trials have consistently suggested that 1 to 2 million cells is a sufficient dose. Therefore, for this trial each patient-specific batch of DC-ATA will be divided into aliquots containing 2 million DC-ATA cells (prior to cryopreservation), and after the initial series of three weekly injections, subsequent injections will be administered up to 18 months from the first injection. If the product is used up, a cryopreserved cell line can be re-expanded and an additional leukapheresis procedure performed in order to make more AV-GBM-1 or MC control, if the patient and their physician wish to continue treatment. For those who were randomized to AV-GBM-1, a GBM cell culture would be re-established from a cryopreserved sample of the original cell line. If for some reason the cell line cannot be reestablished, then patients randomized to the AV-GBM-1 arm would receive injections of their monocytes with GM-CSF to preserve the double-blind conditions.

Patients who are confirmed to have experienced PD while on study must discontinue AV-GBM-1 treatment.

The intent is to enroll approximately 1,120 patients for tumor collection to have 672 patients who are eligible for treatment at the time of randomization and who have granted consent for participation. Because of the lack of toxicity, there are no restrictions related to performance status or blood tests at the time of treatment. The key endpoint is OS from date of randomization; secondary endpoints are OS and PFS from date of first injection. Date of PFS will be determined by the principal investigator at each site.

AV-GBM-1 vs Control as Adjunctive Therapy Following Surgery and RT/TMZ in Newly Diagnosed GBM

Randomized Phase 3 Trial of Standard Care Plus AV-GBM-1 vs Autologous Monocytes as Adjunctive Therapy Following Primary Surgery Plus Concurrent Radiation-temozolomide in Patients With Newly Diagnosed Glioblastoma

Aivita Biomedical, Inc.

Carbon Ion Radiotherapy to the Macroscopic Tumor 6 x 3 Gy E up to 18 Gy E

Proton Radiotherapy to the Macroscopic Tumor 5 x 2 Gy E up to 10 Gy E (Standard dose) applied after 48-52 Gy photon radiotherapy

Carbon ion Radiotherapy up to 18 Gy E in 3 Gy E fractions to the macroscopic tumor

Carbon Ion Radiotherapy

Proton Radiotherapy up to 10 Gy E in 2 Gy E fractions to the macroscopic tumor

Proton Radiotherapy

Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months.

Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.

First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective.

In the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E.

Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety.

Study design

The purpose of the trial is to compare a carbon ion boost to a proton boost delivered to the macroscopic tumor in combination with combined radiochemotherapy with TMZ in patients with primary GBM.

The aim of the study is to compare overall survival as a primary endpoint, and progression free survival, toxicity and safety as secondary endpoints.

Focus of the analysis is to evaluate the change in overall survival and local control by carbon ion radiotherapy. Therefore, the aim of the trial is to evaluate the improvement in outcome due to effect of the altered biology of carbon ions on GBM. Chemotherapy with TMZ is considered standard treatment and is administered continuously as it would be applied in standard patient care outside any trial.

Trial Design The trial will be performed as a single-center two-armed randomized Phase II study.

Patients fulfilling the inclusion criteria will be randomized into two arms:

Arm A - Experimental Arm Carbon Ion Radiation Therapy as a Boost to the macroscopic tumor Total Dose 18 Gy E, 6 fractions, 3 Gy E single dose

Arm B - Standard Arm Proton Radiation Therapy as a Boost to the macroscopic tumor Total Dose 10 Gy E, 5 fractions, 2 Gy E single dose

Standard chemotherapy with TMZ will be continued during the experimental and standard arm in conventional dosing of 75 mg/m2 per day.

Carbon Ion Radiotherapy for Primary Glioblastoma

Randomized Phase II Study Evaluating a Carbon Ion Boost Applied After Combined Radiochemotherapy With Temozolomide Versus a Proton Boost After Radiochemotherapy With Temozolomide in Patients With Primary Glioblastoma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LAM561 With RT and TMZ for Adults With Glioblastoma	NCT04250922	Primary Gliobla... Glioblastoma Mu...	LAM561 TMZ RT	18 Years - 75 Years	Laminar Pharmaceuticals
AV-GBM-1 vs Control as Adjunctive Therapy Following Surgery and RT/TMZ in Newly Diagnosed GBM	NCT05100641	Primary Gliobla...	AV-GBM-1 Autologous mono...	18 Years -	Aivita Biomedical, Inc.
Carbon Ion Radiotherapy for Primary Glioblastoma	NCT01165671	Primary Gliobla...	Carbon Ion Radi... Proton Radiothe...	18 Years -	University Hospital Heidelberg
Carbon Ion Radiotherapy for Primary Glioblastoma	NCT01165671	Primary Gliobla...	Carbon Ion Radi... Proton Radiothe...	18 Years -	University Hospital Heidelberg
LAM561 With RT and TMZ for Adults With Glioblastoma	NCT04250922	Primary Gliobla... Glioblastoma Mu...	LAM561 TMZ RT	18 Years - 75 Years	Laminar Pharmaceuticals
LAM561 With RT and TMZ for Adults With Glioblastoma	NCT04250922	Primary Gliobla... Glioblastoma Mu...	LAM561 TMZ RT	18 Years - 75 Years	Laminar Pharmaceuticals

Spots Global Cancer Trial Database for primary glioblastoma