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
13/04/2025
Date data sharing statement initially provided
27/01/2023
Date results provided
13/04/2025
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 weekly
Arm 5 - Niraparib and AK104: Niraparib: 200mg daily taken orally (tablet), for a maximum of 3 cycles (each cycle is 28 days), AK104: 6mg/kg as Intravenous injection, once every 2 weeks. AK104 and Niraparib is taken simultaneously in combination.

Participants will continue to receive treatment until disease progression is documented or when the participants experience intolerable toxicity or withdraw from the study 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] 417745 0
Health Related Quality of Life using the EORTC BN20 questionnaire
Timepoint [2] 417745 0
Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraws from the study 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 [3] 414764 0
Overall objective Response (OOR) Rate assessed by RANO 2.0 criteria
Timepoint [3] 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 [4] 414765 0
Health Related Quality of Life using the EORTC QLQ-C30 questionnaires
Timepoint [4] 414765 0
Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraws from the study 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. Previously received a conventional treatment regimen comprising radical dose radiotherapy with concurrent or sequential alkylating chemotherapy.
4. Sequential MRIs within 12 months showing disease progression post radiotherapy and chemotherapy as per RANO 2.0 (most notably a 25% increase in T2/FLAIR area, a 25% increase in existing enhancing disease and/or a new measurable enhancing disease) AND without any intervening treatment (defined as including but not limited to surgery, radiotherapy and systemic therapy).
5. a. Suitable for therapeutic resection or biopsy with adequate tissue for successful molecular profiling.
b. Alternatively, participants with prior resection may be included if they meet all other inclusion criteria and the following criteria is met:
i. Tissue resected within 3 weeks prior to study screening, is available for molecular profiling and translational research (block/s or 15-25 slides or as approved by the International Study Chair or their delegate by contacting the LUMOS2 Coordinating Centre prior to study screening
ii. The following bloods can be provided: whole blood (5mL), serum (5mL), plasma (15 mL) and cell pellet, obtained up to 1 week prior to resection) from samples collected at the external site using their approved biobanking processes, or as pre-approved by the International Study Chair or their delegate by contacting the LUMOS2 Coordinating Centre prior to study screening commencing.
iii. No intervening anti-tumour treatments are allowed between resection and study enrolment. (NOTE: Participants who are molecularly profiled outside the LUMOS2 trial will not be eligible even if the above conditions are met)).
iv. The above tissue and blood samples, as well as the related consent documents, are provided to the LUMOS-2 study.
6. For participants who meet all requirements in i-iii above except for the 3 week window for tissue resection, participants can be enrolled at the discretion of the International Study Chair or delegate by contacting the LUMOS2 Coordinating Centre prior to study screening.ECOG performance status 0-2.
7. 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 participants who are in principle wishing to take part in a treatment arm if they are found to be eligible following molecular profiling.
8. Signed, written informed consent for LUMOS2 molecular profiling (and linkage to Medicare records for Australian Participants).


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.

Arm 3 - 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.

Arm 5 - Niraparib and 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 (within 7 days prior to first administration of study drug).
i) 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).
ii) Liver function; ALT/AST less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5xULN.
iii) 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 molecular profiling through the Cancer Screening Program (CaSP) for Australian patients. (Prior molecular profiling through the Molecular Screening and Therapeutics study (MoST) is NOT an exclusion criterion but requires confirmation of eligibility for trial screening by the International Study Chair or their delegate by contacting the LUMOS2 Coordinating Centre prior to study enrolment).
2. Prior treatment with bevacizumab.
3. Intra-surgical treatments (e.g., oncolytic virus administration, Gliadel wafers) at their last craniotomy prior to study enrolment.
4. Participants have had radiotherapy encompassing >20% of the bone marrow within 2 weeks or any radiation therapy within 1 week before Day 1 of protocol therapy.
5. 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.
6. Unable (e.g., due to pacemaker or ICD device) or unwilling to have a contrast-enhanced MRI of the head.
7. 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)).
8. Severely immunocompromised patients are not allowed.
9. 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 enrolment. 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.

Arm 3 - 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.

Arm 5 - Niraparib and 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. Participant is at an increased bleeding risk due to concurrent conditions (e.g., major injuries or major surgery within the past 28 days before start of study treatment).
6. Participants have received a transfusion (platelets or red blood cells) or colony-stimulating factors (e.g., granulocyte macrophage colony-stimulating factor or recombinant erythropoietin) within 4 weeks before the first dose of study treatment except where directly related to surgery.
7. Participants have leptomeningeal disease, carcinomatous meningitis, or radiographic signs of central nervous system haemorrhage.
8. Participants have current active pneumonitis or any history of pneumonitis requiring steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the study.
9. Participants have systolic BP >140 mmHg or diastolic BP >90 mmHg that has not been adequately treated or controlled.
10. Any patient with prior history of Posterior Reversible Encephalopathy Syndrome (PRES).
11. Concomitant medications which may interact with the investigational product(s) in the opinion of the physician.
12. 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 study treatment. 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.

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
76
Accrual to date
35
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 25937 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 23440 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 23439 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 23444 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 23438 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [6] 23442 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [7] 27751 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [8] 23373 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [9] 25939 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [10] 25938 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [11] 23443 0
Royal Hobart Hospital - Hobart
Recruitment hospital [12] 23441 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [13] 27752 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 41771 0
2298 - Waratah
Recruitment postcode(s) [2] 38841 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 38758 0
3084 - Heidelberg
Recruitment postcode(s) [4] 38842 0
2065 - St Leonards
Recruitment postcode(s) [5] 43940 0
6009 - Nedlands
Recruitment postcode(s) [6] 38844 0
3168 - Clayton
Recruitment postcode(s) [7] 38843 0
3000 - Melbourne
Recruitment postcode(s) [8] 38846 0
7000 - Hobart
Recruitment postcode(s) [9] 38847 0
4029 - Herston
Recruitment postcode(s) [10] 41770 0
2170 - Liverpool
Recruitment postcode(s) [11] 38845 0
3065 - Fitzroy
Recruitment postcode(s) [12] 41772 0
5042 - Bedford Park
Recruitment postcode(s) [13] 43941 0
4102 - Woolloongabba
Recruitment outside Australia
Country [1] 26966 0
Canada
State/province [1] 26966 0
British Columbia
Country [2] 26965 0
Canada
State/province [2] 26965 0
Manitoba

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
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
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
[email protected]
Contact person for public queries
Name 122379 0
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
[email protected]
Contact person for scientific queries
Name 122380 0
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
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• 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 [email protected].


Conditions for requesting access:
• -

What individual participant data might be shared?
• Participant data supporting the publication results and participant data relating to primary outcomes, secondary outcomes, and safety data.

What types of analyses could be done with individual participant data?
• Any type of analysis and will be assessed on a case-by-case basis

When can requests for individual participant data be made (start and end dates)?
From:
Data are available straight after publication
Data are available for an indefinite time
Start date: 31 Jul 2027(approx)
End date: Unknown





To:
-

Where can requests to access individual participant data be made, or data be obtained directly?
• Please contact the LUMOS2 study team, at [email protected]




Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Other filesYeshttps://doi.org/10.1136/bmjopen-2024-087922 https://bmjopen.bmj.com/content/15/2/e087922

Documents added automatically
No additional documents have been identified.