None listed
Conditions
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, the oral medication Selinexor administered once weekly, or the oral medication Niraparib administered once daily in combination with the intravenous infusion AK104 administered once every 2 weeks. Treatment will continue until disease progression is documented or until participants experience intolerable toxicity or withdraw from the study 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.
Interventions
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 p
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.
Sponsors
The University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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.
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.
Outcome results
None listed