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

An interventional study requiring a study-specific craniotomy and molecular testing to identify mutations. 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

Eligible Population: 

1. Adults, aged 18 years and older

2. Histologically confirmed glioma, IDH-mutant, histologically grade 2 or 3 at initial diagnosis; 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.

3. Has evidence of progressive disease.

4. Had prior treatment with radiotherapy and alkylating chemotherapy.

5. ECOG performance status 0-2.

6. No prior treatment with bevacizumab.

Substudy status: Recruiting

Registration number: ACTRN12623000096651

Title: A Single Arm, Open-label, Phase II Signal-seeking Trial of Tiragolumab and Atezolizumab in Patients With Advanced Solid Tumours

The aim of this study is to evaluate the effect of 2 monoclonal antibodies, tiragolumab and atezolizumab, in patients with locally advanced solid cancers which cannot be removed by surgery or have spread.

Eligible Population: 

• Histologically or cytologically confirmed locally advanced unresectable or metastatic solid tumour. Non-small cell lung cancer is excluded
• Exhausted all available standard therapy or not suitable for standard therapy (including targeted therapies) for the tumour
• Sufficient and accessible tumour tissue for panel sequencing, PD-L1 and TIL testing, and tertiary objectives
• Tumour biomarker criteria predictive of immune response defined by presence of one or more of the following: 
  • Tumour Mutation Burden ≥ 10 mutations per megabase
  • Tumour and immune cell PD-L1 expression (TAP score) > 20% high or PD-L1 (CD274) amplification >6 copy number alterations
  • Tumour and immune cell PD-L1 expression (TAP score) 5-20%
  • Tumour Infiltrating Lymphocytes (TILs) (CD3+CD8+) ≥ 5% [CLOSED]
• Prior use of approved or investigational anti-TIGIT therapy is not eligible.
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies is not eligible.

Substudy status: Recruiting

Registration number: NCT06003621

Title: An Open-Label Study to Assess the Preliminary Efficacy and Safety of RXC004 (Zamaporvint) in Patients with Advanced Pancreatic cancer that have Progressed following Therapy with Current Standard of Care

The aim of this MoST companion, Phase II, open-label, study to evaluate the preliminary efficacy and safety of RXC004 monotherapy in RNF43 LoF mutation-positive advanced pancreatic tumours (PDAC) that have progressed following standard of care treatment. This study will follow-on from the Phase 2 the PORCUPINE 2 study (RXC004/003) which contained a RNF43 LoF mutation-positive PDAC module (Module 1).

Eligible Population: 

Inclusion Criteria: 

• Histological documentation of advanced (unresectable)/metastatic (Stage III/IV) pancreatic ductal adenocarcinoma, with documented loss of function tumour mutation in RNF43
• Patients must have received one prior systemic treatment for advanced (unresectable)/metastatic pancreatic ductal adenocarcinoma (Stage III/IV), with clear evidence of radiological disease progression.
• At least one lesion that is measurable by RECIST 1.1 at baseline (within 6 weeks prior to start of study treatment). The measurable lesion must not be chosen for the mandatory and optional biopsies.
• Baseline biopsy; Patients must have at least one lesion suitable for baseline biopsy at screening (which must not be a target lesion for RECIST 1.1)
  • The baseline* biopsy is mandatory and must be performed before study treatment commences, except in exceptional circumstances where biopsy is not technically feasible. All patients without a baseline sample must be approved by Sponsor before starting study treatment
  • * An archival biopsy that was taken after completion of all prior standard of care treatments will be accepted as a baseline biopsy.

Exclusion Criteria: 

• Patients who have any history of an active (requiring treatment) other malignancy (except any in-situ carcinoma, non-melanoma skin carcinoma, and early prostate cancer with a normal PSA) within 2 years of study entry.
• Patients with known or suspected brain metastases
• Patients with a contra-indication for denosumab treatment including:
  • Known hypersensitivity to denosumab or any of the excipients
  • Severe untreated hypocalcaemia
  • Unhealed lesions from dental or oral surgery

Substudy status: Recruiting

Registration number: ACTRN12624000588594