LUMOS2: Low & Anaplastic Grade Glioma Umbrella Study of Molecular Guided TherapieS

ACTRN 12623000096651

Brief Summary

This study aims to evaluate a new approach to the treatment of patients with lower gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells glioma that has started to grow again (i.e. is recurrent) following your initial treatment.

Intervention / Treatment

• Paxalisib.
• AK104.
• Selinexor.
• Niraparib and AK104.

Inclusion Criteria:

Molecular profiling:

1. Adults, aged 18 years and older.
2. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosisthe process of identifying a disease based on signs and symptoms, patient history and medical test results (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 dosethe amount of medication taken radiotherapy with concurrent or sequential alkylating chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells.
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 surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence, radiotherapy and systemic therapy).
5. a. Suitable for therapeutic resectionsurgical removal of tissue or part/all of an organ or biopsyremoval of a section of tissue to analyse for cancer cells with adequate tissuea group of cells that work together to perform a function 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:
   • Tissue resected within 3 weeks prior to study screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer 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
   • The following bloods can be provided: whole bloodthe red bodily fluid that transports oxygen and other nutrients around the body (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.
   • 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)).
   • 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 consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. 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 marrowsoft, spongy tissue found in bones that makes blood cells function; plateletssmall disc-shaped blood cells that clump together to form clots to stop bleeding 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 Tumoura tissue mass that forms from groups of unhealthy cells 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.