Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000096651
Ethics application status
Approved
Date submitted
25/10/2022
Date registered
27/01/2023
Date last updated
16/06/2024
Date data sharing statement initially provided
27/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
LUMOS2: Low & Anaplastic Grade Glioma Umbrella Study of Molecular Guided TherapieS
Scientific title
LUMOS2: Low & Anaplastic Grade Glioma Umbrella Study of Molecular Guided TherapieS
Secondary ID [1] 308189 0
CTC0378
Secondary ID [2] 308190 0
COGNO2201
Universal Trial Number (UTN)
Trial acronym
LUMOS2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Grade 2 Glioma 327930 0
Grade 3 Glioma 327931 0
Condition category
Condition code
Cancer 324999 324999 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants who consent to the study, will have a study-specific craniotomy and the tissue collected will be used to undergo molecular testing to identify mutations. The results of molecular testing will be reviewed by the LUMOS2 Molecular Tumour Advisory Board, and a treatment recommendation will be provided. If the participant is found to have a molecular profile that matches to one of the treatment arms available, they will be consented to and screened for the matched treatment arm. If the participant does not have a molecular profile that matches a treatment arm, they will be randomised to one of the treatment arms that does not require a matched mutation.

The following treatment arms are available under this protocol:
Arm 1 - Paxalisib: 45mg taken orally (capsule), once daily, for a 28 day cycle. If tolerated, after cycle 1 this will increase to 60mg daily.
Arm 2 - AK104: 6mg/kg as Intravenous injection, once every 2 weeks
Arm 3 - Selinexor: 80mg taken orally (tablet), once daily
Participants will continue to receive treatment until disease progression is documented or when the participants experience intolerable toxicity or withdraw for another reason.
Intervention code [1] 324641 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332811 0
Progression free survival at 6 months
Timepoint [1] 332811 0
Progression Free Survival is defined as the time from the date of study enrolment to date of first documented evidence of disease progression or death from any cause. This is assessed via 8 weekly MRI scans until disease progression/death and will be estimated using the Kaplan-Meier method.
Secondary outcome [1] 414763 0
Overall survival
Timepoint [1] 414763 0
For the duration of the study. From the date of first diagnosis to date of death from any cause, or the date of last known follow-up alive
Secondary outcome [2] 414764 0
Overall objective Response (OOR) Rate assessed by modified RANO criteria
Timepoint [2] 414764 0
ORR is the proportion of participants who achieve partial or complete response, as assessed by 8-weekly MRI scans prior to disease progression/death
Secondary outcome [3] 414765 0
Health Related Quality of Life using the EORTC QLQ-C30 questionnaires
Timepoint [3] 414765 0
Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraws for another reason apart from disease progression. After treatment discontinuation, the health-related quality of life will be assessed at every 12 weeks until disease progression.
Secondary outcome [4] 417745 0
Health Related Quality of Life using the EORTC BN20 questionnaire
Timepoint [4] 417745 0
Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraws for another reason apart from disease progression. After treatment discontinuation, the health-related quality of life will be assessed at every 12 weeks until disease progression.

Eligibility
Key inclusion criteria
Molecular profiling:
1. Adults, aged 18 years and older
2. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosis (i.e., without necrosis or microvascular proliferation); including CDKN2A/B homozygous deleted IDH-mutant astrocytomas but not IDH-wildtype diffuse astrocytomas with any of TERT promoter mutation, EGFR amplification and/or +7/-10 copy number changes (i.e., molecular features of glioblastoma).
3. Has evidence of progressive disease (defined as new contrast-enhancing tumour and/or 25% increase in the size of the T2/FLAIR area compared to prior imaging after prior treatment with radiotherapy and chemotherapy; with a clinical indication for neurosurgery).
4. Prior treatment with radiotherapy and alkylating chemotherapy, defined as either sequential therapy with CNS radiotherapy then an akylating agent, or concurrent CNS radiotherapy with an alkylating agent.
5. ECOG performance status 0-2.
6. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments; It is the intention that molecular profiling is performed for patients who are in principle wishing to take part in a treatment arm if they are found to be eligible following molecular profiling.
7. Signed, written informed consent (LUMOS2 molecular profiling and linkage to Medicare records).



Additional inclusion criteria for:
Arm 1 - Paxalisib:
1. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosis (i.e., without necrosis or microvascular proliferation); including CDKN2A/B homozygous deleted IDH-mutant astrocytomas but not IDH-wildtype diffuse astrocytomas with any of TERT promoter mutation, EGFR amplification and/or +7/-10 copy number changes (i.e., molecular features of glioblastoma).
2. Adequate recovery from surgery in the opinion of the treating physician (as evidenced by ECOG performance status 0-2).
3. Adequate organ system function post-surgery as assessed by the following minimal laboratory requirements.
a) Bone marrow function; platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 90g/L (5.6mmol/L)
b) Liver function; ALT/AST less than or equal to 3 x ULN and total bilirubin less than or equal to 1.5xULN
c) Renal function; serum creatinine less than or equal to 1.5xULN
4. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
5. LUMOS2 Molecular Tumour Advisory Panel (MTAP) report confirming eligibility to this treatment arm.
6. Signed, written informed consent

Arm 2 - AK104:
1. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosis (i.e., without necrosis or microvascular proliferation); including CDKN2A/B homozygous deleted IDH-mutant astrocytomas but not IDH-wildtype diffuse astrocytomas with any of TERT promoter mutation, EGFR amplification and/or +7/-10 copy number changes (i.e., molecular features of glioblastoma).
2. Adequate recovery from surgery in the opinion of the treating physician (as evidenced by ECOG performance status 0-2).
3. Adequate organ system function post-surgery as assessed by the following minimal laboratory requirements
a. Bone marrow function; platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 90g/L (5.6mmol/L).
b. Liver function; ALT/AST less than or equal to 3 x ULN and total bilirubin less than or equal to 1.5xULN.
c. Renal function; serum creatinine less than or equal to 1.5xULN.
4. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments; and
5. LUMOS2 Molecular Tumour Advisory Panel (MTAP) report confirming eligibility to this treatment arm
6. Signed, written informed consent.

Arm3 - Selinexor:
1. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosis (i.e., without necrosis or microvascular proliferation); including CDKN2A/B homozygous deleted IDH-mutant astrocytomas but not IDH-wildtype diffuse astrocytomas with any of TERT promoter mutation, EGFR amplification and/or +7/-10 copy number changes (i.e., molecular features of glioblastoma).
2. Adequate recovery from surgery in the opinion of the treating physician (as evidenced by ECOG performance status 0-2).
3. Adequate organ system function post-surgery as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug).
a) Bone marrow function; platelets greater than or equal to 100 x 109/L, ANC greater than or equal to 1.5 x 109/L, and haemoglobin greater than or equal to 90g/L (5.6mmol/L).
b) Liver function; ALT/AST less than or equal to 3 x ULN and total bilirubin less than or equal to 1.5xULN.
c) Renal function; serum creatinine less than or equal to 1.5xULN.
4. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments; and
5. LUMOS2 Molecular Tumour Advisory Panel (MTAP) report confirming eligibility to this treatment arm
6. Signed, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Molecular profiling:
1. Prior treatment with bevacizumab
2. Intra-surgical treatments (e.g., oncolytic virus administration, Gliadel wafers) at their last craniotomy prior to study enrolment.
3. Comorbidities or conditions (e.g., psychiatric) that may compromise assessment of key outcomes or in the opinion of the physician limit the ability of the participant to comply with the protocol.
4. Unable (e.g., due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head
5. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy (Those with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy))
6. Pregnancy, lactation, or inadequate contraception. Persons who are able to become pregnant, and having sexual relationships in which they may become pregnant, must use a reliable means of contraception and must have a negative pregnancy test done within 7 days prior to registration. Persons who are having sexual relationships in which their partner may become pregnant must have been surgically sterilised or use a (double if required) barrier method of contraception.

Additional exclusion criteria for:
Arm 1 - Paxalisib:
1. Intra-surgical treatments (e.g., oncolytic virus administration, Gliadel wafers) at their last craniotomy prior to study enrolment;
2. Presence of any metastatic tumours at the time of craniotomy that are not consistent with original glioma diagnosis.
3. Prior IDH inhibitor therapy within 4 weeks of first dose of LUMOS2 investigational treatment.
4. Prior investigational agents within 4 weeks of first dose of LUMOS2 investigational treatment.
5. Concomitant medications which may interact with the investigational product(s) in the opinion of the physician
6. Baseline QT interval >470msec or clinically significant cardiac history (myocardial infarction or symptomatic bradycardia, active congestive heart failure or angina pectoris).

Arm 2 - AK104:
1. Intra-surgical treatments (e.g., oncolytic virus administration, Gliadel wafers) at their last craniotomy prior to study enrolment
2. Presence of any metastatic tumours at the time of craniotomy that are not consistent with original glioma diagnosis.
3. Prior IDH inhibitor therapy within 4 weeks of first dose of LUMOS2 investigational treatment.
4. Prior investigational agents within 4 weeks of first dose of LUMOS2 investigational treatment.
5. Concomitant medications which may interact with the investigational product(s) in the opinion of the physician.
6. Clinically significant symptomatic auto-immune disease that may predispose patient to immune-related adverse events in the opinion of the treating physician.

Arm3 - Selinexor:
1. Intra-surgical treatments (e.g., oncolytic virus administration, Gliadel wafers) at their last craniotomy prior to study enrolment;
2. Presence of any metastatic tumours at the time of craniotomy that are not consistent with original glioma diagnosis.
3. Prior IDH inhibitor therapy within 4 weeks of first dose of LUMOS2 investigational treatment.
4. Prior investigational agents within 4 weeks of first dose of LUMOS2 investigational treatment.
5. Concomitant medications which may interact with the investigational product(s) in the opinion of the physician.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The results of the participant's molecular sequencing will be used to allocate the participants to the study treatment arms. If the participant does not have a mutation that has a targeted treatment, the participant will be randomised to a treatment arm that does not require a matched mutation.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
LUMOS2 is a multi-arm, phase 2, biomarker-directed, signal-seeking, umbrella clinical trial.
Prior studies in similar populations have shown 6-month Progression Free Survival (PFS) of approximately 36% (range 30-40%) and a rate lower than this would not be considered worthwhile. Nineteen participants will be recruited into each treatment arm, and have 80% power at 5% one-sided alpha to rule out a rate of 36% if the true rate is 65%, using a one-sample exact binomial test, and will allow estimation of 6-month PFS with a 95% confidence interval of maximum width ±21%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/09/2023
Actual
11/09/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
57
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,VIC
Recruitment hospital [1] 23373 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 23438 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [3] 23439 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 23440 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [5] 23441 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [6] 23442 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [7] 23443 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 23444 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [9] 25937 0
Liverpool Hospital - Liverpool
Recruitment hospital [10] 25938 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [11] 25939 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 38841 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 38842 0
2065 - St Leonards
Recruitment postcode(s) [3] 41770 0
2170 - Liverpool
Recruitment postcode(s) [4] 41771 0
2298 - Waratah
Recruitment postcode(s) [5] 38843 0
3000 - Melbourne
Recruitment postcode(s) [6] 38845 0
3065 - Fitzroy
Recruitment postcode(s) [7] 38758 0
3084 - Heidelberg
Recruitment postcode(s) [8] 38844 0
3168 - Clayton
Recruitment postcode(s) [9] 38847 0
4029 - Herston
Recruitment postcode(s) [10] 41772 0
5042 - Bedford Park
Recruitment postcode(s) [11] 38846 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 312445 0
Government body
Name [1] 312445 0
Australian Government, Department of Health and Aged Care - Medical Research Future Fund
Country [1] 312445 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 314023 0
None
Name [1] 314023 0
Address [1] 314023 0
Country [1] 314023 0
Other collaborator category [1] 282456 0
Other Collaborative groups
Name [1] 282456 0
Cooperative Trials Group for Neuro-Oncology
Address [1] 282456 0
NHMRC Clinical Trials Centre
Level 6, Lifehouse
119-143 Missenden Road
Camperdown, NSW 2050
Country [1] 282456 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311791 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 311791 0
Suite 210A
RPA Medical Centre
Cnr Missenden Road and Carillon Avenue
NEWTOWN NSW 2042
Ethics committee country [1] 311791 0
Australia
Date submitted for ethics approval [1] 311791 0
25/10/2022
Approval date [1] 311791 0
24/01/2023
Ethics approval number [1] 311791 0
2022/ETH02230

Summary
Brief summary
This study aims to evaluate a new approach to the treatment of patients with lower grade glioma that has started to grow again (i.e. is recurrent) following your initial treatment.

Who is it for?
You may be eligible to join this study if you are aged 18 years or older, with histologically-confirmed grade 2 or 3 glioma at initial diagnosis, and with evidence of progressive disease after initial treatment.

Study details
For each participant, the study will involve taking a sample of tumour tissue during surgery, which will be screened for biomarkers. The results of this testing will then be used by a panel of experts who will make a treatment recommendation. If you have a mutation that matches one of the treatment arms, this will be recommended to you. If you do not have a mutation that matches one of the treatment arms, you will be randomised (i.e. allocated by chance) to one of the treatments that does not require a matching mutation. The study treatments available in LUMOS2 are: the oral medication Paxalisib administered once daily, the intravenous infusion AK104 administered once every 2 weeks, or the oral medication Selinexor administered once daily.
Treatment will continue until disease progression is documented or until participants experience intolerable toxicity or withdraw for another reason. During treatment, participants will undergo an MRI scan every 8 weeks to assess for disease progression and response to treatment, and will complete questionnaires regarding their quality of life.

It is hoped that screening tumour tissue for specific biomarkers to direct targeted treatment will be effective, safe, and cost-effective for the management of patients with recurrent lower grade glioma.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122378 0
Prof Hui Gan
Address 122378 0
Austin Health, 145 Studley Road, Heidelberg, VIC, 3084
Country 122378 0
Australia
Phone 122378 0
+61 3 9496 5000
Fax 122378 0
Email 122378 0
hui.gan@onjcri.org.au
Contact person for public queries
Name 122379 0
Dr LUMOS2 Coordinator
Address 122379 0
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 122379 0
Australia
Phone 122379 0
+61 2 9562 5000
Fax 122379 0
Email 122379 0
lumos2.study@sydney.edu.au
Contact person for scientific queries
Name 122380 0
Dr LUMOS2 Coordinator
Address 122380 0
NHMRC Clinical Trials Centre
Lifehouse Level 6
119–143 Missenden Road
Camperdown NSW 2050
Country 122380 0
Australia
Phone 122380 0
+61 2 9562 5000
Fax 122380 0
Email 122380 0
lumos2.study@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Participant data supporting the publication results and participant data relating to primary outcomes, secondary outcomes, and safety data.
When will data be available (start and end dates)?
Data are available straight after publication
Data are available for an indefinite time
Start date: 31 Jul 2027(approx)
End date: Unknown



Available to whom?
Data are potentially available to:
- Researchers from not-for-profit organisations
- Commercial organisations
- Other
Based in:
- Any location

Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, please contact lumos2.study@sydney.edu.au.
Available for what types of analyses?
Any type of analysis and will be assessed on a case-by-case basis
How or where can data be obtained?
Please contact the LUMOS2 study team, at lumos2.study@sydney.edu.au




What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.