Patient case: 45-year-old female with Melanoma. Genetic variant: BRAF (V600E), CDKN2A Deletion. Other conditions: None.

Clinical trial: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer

Summary: This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, randomised Phase 1b study in patients with muscle invasive bladder cancer (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents in patients with muscle invasive bladder cancer.
  The study will consist of a number of study modules (substudies), each evaluating the safety and tolerability of a specific agent or combination.

Detailed description: This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, randomised Phase 1b study in patients with muscle invasive bladder cancer (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents in patients with muscle invasive bladder cancer. The study will consist of a number of study modules (sub-studies), each evaluating the safety and tolerability of a specific agent or combination in patients whose tumours express specific mutations relevant to the molecules under investigation and whose disease has progressed following prior therapy. The allocation of patients to specific modules will depend on the specific eligible mutations identified in their tumours.
  Module A includes an AZD4547 monotherapy arm and a durvalumab + AZD4547 combination therapy arm. Patients who receive AZD4547 monotherapy will have the option to cross over to durvalumab as a monotherapy treatment at the point of objective progression. Module A will investigate the safety and tolerability of durvalumab given intravenously, in combination with AZD4547 given orally to selected patients with muscle invasive bladder cancer with tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor receptor fusions and whose disease has progressed following prior therapy. Specifically the following fibroblast growth factor receptor 3 activating mutations are eligible, R248C, S249C, G370C, Y373C, S371C, G3780R, as are fibroblast growth factor receptor 1, 2, 3 gene fusions resulting in removal of the c-terminal of the fibroblast growth factor receptor while encoding an intact tyrosine kinase domain, an example being the fibroblast growth factor receptor 3-transforming acidic coiled-coil 3 fusions identified in bladder cancer and glioblastoma. Module A will evaluate the durvalumab + AZD4547 combination dose(s) for further clinical evaluation and assess the safety, tolerability and efficacy of AZD4547 given orally to selected patients with muscle invasive bladder cancer who have progressed following prior therapy. In the combination arm, a maximum tolerated dose will be defined by dose-limiting toxicity. An expansion cohort(s) in Module A will enroll additional patients to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected AZD4547 plus durvalumab dose(s). Patients who receive AZD4547 as monotherapy will have the option to cross over to durvalumab as monotherapy at the point of objective progression as long as the investigator believes it is in the patient's interest to continue MEDI4736 monotherapy.
  Module B will evaluate durvalumab + olaparib combination dose(s) to confirm the safety and tolerability of durvalumab given intravenously in combination with olaparib (AZD2281). Olaparib will be given orally to selected patients with muscle invasion bladder cancer (MIBC) whose tumors have deleterious mutations, deletions or truncations in any one of a panel of homologous recombination repair (HRR) genes, and whose disease had progressed following prior therapy.
  Module C will evaluate durvalumab + AZD1775 combination doses(s) to confirm the safety and tolerability of durvalumab given intravenously, in combination with AZD1775 given orally to selected patients with MIBC whose tumours have mutations in genes involved in cell cycle regulation (eg, loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or amplification of cyclin E1 or MYC family genes).
  Module D will evaluate durvalumab monotherapy treatment to confirm the safety and tolerability of durvalumab given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C. This sub-study will not be restricted to any PD-L1 defined sub-population and it is intended to perform retrospective analysis of PD-L1 so that patients with positive PD-L1 status are included in this monotherapy module.
  Module E will evaluate the safety and tolerability of durvalumab given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose disease has progressed following prior therapy. Patients who enter this sub study will be those whose tumours do not show mutations that would be eligible for other study modules, with the exception of the following mutations that have potential to respond to an mTOR inhibitor: RICTOR amplification, or TSC1/2 mutations.

Eligibility: Inclusion Criteria for all Modules:
  1. M/F ≥18
  2. Metastatic MIBC
  3. 2nd/3rd line
  4. Failed adjuvant/neo-adjuvant chemotherapy <1 yr
  5. 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
  7. WHO perf. status 0-1
  Specific to Module A:
  1. M/F ≥25
  2. Confirmation of FGFR3 mutation or FGFR fusion
  Specific to Module B:
  1. Hgb ≥ 10 g/dL
  2. Deleterious mutation, deletion or truncation in any HRR genes
  Specific to Module C:
  1. Tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL or MYCN genes
  Specific to Module E:
  1. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose
  Exclusion Criteria for all Modules:
  1. Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 wks, or radiotherapy for palliation <2 wks, any study drugs <30 days.
  2. Major surgery <4 wk
  3. Unresolved toxicities from prior therapy
  4. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
  5. Immunosuppressive drugs <28 days
  6. Any of the following:
  -  Autoimmune disease ≤2 yr
  -  IBD
  -  Primary immunodeficiency
  -  Organ transplant requiring immunosuppressives
  7. Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks
  8. Severe or uncontrolled systemic disease
  9. Any of the following:
  -  Mean QTc ≥470 ms
  -  Abnormalities in resting ECG
  -  Factors that increase the risk of QTc prolongation or arrhythmia
  -  Uncontrolled hypertension or hypotension
  -  LVEF <55%
  -  Atrial fibrillation
  -  NYHA Grade II-IV
  -  Severe valvular disease
  -  Uncontrolled angina
  -  Stroke/TIA <6 months
  -  Acute coronary syndrome <6 months
  10. Any of the following laboratory values:
  -  ANC <1.5x10(exp9)/L
  -  Platelets <100x10(exp9)/L
  -  Hgb <9.0 g/dL
  -  ALT >2.5xULN or >5xULN with liver mets
  -  Total bilirubin >1.5 times ULN or with Gilbert's disease ≥2×ULN
  -  Creatinine >1.5xULN concurrent with creatinine clearance <50 mL/min
  -  Corrected CA >ULN
  -  PO4 >ULN
  11. History of tuberculosis
  12. Live attenuated vaccination <30 days
  For Module A:
  1. Prior exposure to:
  -  Nitrosourea or mitomycin C <6 weeks
  -  Agent with FGFR inhibition as its primary pharmacology
  -  AZD4547
  -  Potent inhibitors/inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 <2 wks
  2. Ophthalmological criteria:
  -  RPED
  -  Laser treatment or intra-ocular injection for macular degeneration
  -  Age-related macular degeneration
  -  Retinal vein occlusion
  -  Retinal degenerative disease
  -  Any other clinically relevant chorioretinal defect
  3. Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection
  For Module B:
  1. Transfusion <120 days
  2. Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4.
  3. Previous treatment with PARP inhibitor, including olaparib
  4. Patients with history of MDS or AML
  For Module C:
  1. Prior exposure to any of the following:
  -  Nitrosourea or mitomycin C <6 wks
  -  Any agent with Wee1 inhibition as its primary pharmacology
  -  Prior treatment with AZD1775
  2. Any drugs or products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with narrow therapeutic index, or moderate to strong inhibitors/inducers of CYP3A4
  3. Herbal preparations
  4. Refractory nausea and vomiting or chronic GI diseases
  5. Cardiac disease <6 months
  For Module E:
  1. Minor surgery <14 days of first dose
  2. Exposure to specific substrates of OATP1B1, OATP1B3, MATE1 and MATE2K <5x half-life) before treatment. Exposure to strong/moderate inhibitors of inducers of CYP3A4/5, Pgp (MDR1) and BRCP if taken within washout periods before the first dose
  3. Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) <14 days prior to receiving treatment
  4. Other mTOR inhibitors
  5. Renal disease or renal tubular acidosis
  6. Uncontrolled Type 1 or 2 diabetes

Relevance to patient case: not relevant