Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of cytochrome P, family , subfamily A, polypeptide  (CYPA) or sensitive CYPA substrates and CYPA substrates with a narrow therapeutic range are not eligible; the use of aprepitant as an antiemetic is prohibited; caution should be exercised with concomitant administration of AZD (MK-) and agents that are sensitive substrates of cytochrome P, family , subfamily C, polypeptide  (CYPC), C and C, or substrates of this enzyme with narrow therapeutic ranges, as well as agents that are inhibitors or substrates of permeability glycoprotein (P-gp)
Currently receiving medications known to be inhibitors of CYPA/. Subjects currently receiving medications of known inducers of CYPA/ or substrates of CYPC/ and CYPA may be excluded.
Inclusion Criteria for all Modules:\n\n          . Metastatic MIBC\n\n          . nd/rd line\n\n          . Failed adjuvant/neo-adjuvant chemotherapy < yr\n\n          .  lesion ? mm at baseline in the longest diameter suitable for accurate repeated\n             measurement\n\n          . WHO perf. status -\n\n        For Module A:\n\n          . M/F ?\n\n          . Confirmation of FGFR mutation or FGFR fusion\n\n        For Module B:\n\n          . Hgb ? g/dL\n\n          . Deleterious mutation, deletion or truncation in any HRR genes\n\n        For Module C:\n\n        . Tumour harbours a deletion or inactivating mutation of the CDKNA or RB genes and/or\n        amplification of CCNE, MYC, MYCL or MYCN genes\n\n        For Module E:\n\n        . Contraception must be sustained throughout treatment with vistusertib and  wks after\n        last dose\n\n        For Module F:\n\n          . Adequate organ and marrow function, defined as Leukocytes ?.x(exp)/L; ANC\n             ?.x(exp)/L; platelets ?x(exp)/L\n\n          . Contraceptive measures must be sustained throughout treatment with AZD and for \n             days after the last dose.\n\n        Exclusion Criteria for all Modules:\n\n          . Immunotherapy, chemotherapy, anticancer agents, radiotherapy < wks, or radiotherapy\n             for palliation < wks, any study drugs < days.\n\n          . Major surgery < wk\n\n          . Unresolved toxicities from prior therapy\n\n          . Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy\n\n          . Immunosuppressive drugs < days\n\n          . Any of the following: Autoimmune disease ? yr; IBD; primary immunodeficiency; organ\n             transplant requiring immunosuppressives\n\n          . Spinal cord compression or brain metastases, treated and stable & not requiring\n             steroids for at least  weeks\n\n          . Severe or uncontrolled systemic disease\n\n          . Any of the following: Mean QTc ? ms; abnormalities in resting ECG; factors that\n             increase the risk of QTc prolongation or arrhythmia; uncontrolled hyper/hypotension;\n             LVEF <%; atrial fibrillation; NYHA Grade II-IV; severe valvular disease;\n             uncontrolled angina; stroke/TIA < months; acute coronary syndrome < months\n\n         . Any of the following laboratory values: ANC <.x(exp)/L; Platelets\n             <x(exp)/L; Hgb <. g/dL; ALT >.xULN or >xULN with liver mets; Total\n             bilirubin >. times ULN or with Gilbert's disease ?ULN; Creatinine >.xULN\n             concurrent with creatinine clearance < mL/min; Corrected Ca >ULN, PO >ULN\n\n         . Active infection including tuberculosis, hepatitis B (HBV), hepatitis C (HCV), or\n             human immunodeficiency virus. Patients with a past or resolved HBV infection are\n             eligible. Patients positive for HCV antibody are eligible only if polymerase chain\n             reaction is negative for HCV RNA.\n\n         . Live attenuated vaccination < days\n\n        For Module A:\n\n          . Prior exposure to: Nitrosourea or mitomycin C < weeks; any agent with FGFR inhibition\n             as its primary pharmacology; AZD; potent inhibitors/inducers of CYPA, inhibitors\n             of CYPD or substrates of CYPA < wks\n\n          . Ophthalmological criteria: RPED; laser treatment or intraocular injection for macular\n             degeneration; age-related macular degeneration; retinal vein occlusion; retinal\n             degenerative disease; other clinically relevant chorioretinal defect\n\n          . Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection\n\n        For Module B:\n\n          . Transfusion < days\n\n          . Concurrent medications that are strong inhibitors of cytochrome P (CYP) A (CYPA)\n             or strong inducers of CYPA.\n\n          . Previous treatment with PARP inhibitor, including olaparib\n\n          . Patients with history of MDS or AML\n\n        For Module C:\n\n          . Prior exposure to any of the following: Nitrosourea or mitomycin C < wks; any agent\n             with Wee inhibition as its primary pharmacology; prior treatment with AZD\n\n          . Any drugs or products known to be sensitive to CYPA substrates or CYPA substrates\n             with narrow therapeutic index, or moderate to strong inhibitors/inducers of CYPA\n\n          . Herbal preparations\n\n          . Refractory nausea and vomiting or chronic GI diseases\n\n          . Cardiac disease < months\n\n        For Module E:\n\n          . Minor surgery < days of first dose\n\n          . Exposure to specific substrates of OATPB, OATPB, MATE and MATEK <x half-life\n             before treatment. Exposure to strong/moderate inhibitors/inducers of CYPA/, Pgp\n             (MDR) and BRCP if taken within washout periods before the first dose\n\n          . Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) < days prior to\n             treatment\n\n          . Other mTOR inhibitors\n\n          . Renal disease or renal tubular acidosis\n\n          . Uncontrolled Type  or  diabetes\n\n        For Module F:\n\n        . AST ? .xULN or ?xULN with liver mets
The following medications are contraindicated or must be used with caution\r\n* Contraindicated:\r\n** Cytochrome P, family , subfamily C, polypeptide  (CYPC) strong and moderate inhibitors\r\n** CYPC inducers\r\n** Cytochrome P, family , subfamily A, polypeptide  (CYPA) strong and moderate inhibitors\r\n** CYPA inducers\r\n** CYPA sensitive substrates\r\n* Exclusions: the following supportive care medications will be allowed will be allowed as they are routinely administered with carboplatin and paclitaxel and have no potential interaction with talazoparib (BMN ): dexamethasone, aprepitant, fosaprepitant, and ondansetron); oral pain medications such as hydrocodone, oxycodone taken on an as needed basis are also permitted\r\n* Transdermal products designed for systemic delivery must be assessed for interaction potential; topical products not designed to provide systemic delivery (including inhaled products, ophthalmologic products and transvaginal preparations) do not need to be considered\r\n* Other contraindicated medications (per above) are not allowed unless close monitoring with labs or drug levels or by symptoms with subsequent dose adjustments is feasible; patients taking these concurrent medications are ineligible unless they can discontinue or switched to alternative medications prior to initiation of the study drug (at least  half-lives)\r\n* Use with caution:\r\n** CYPC sensitive substrates\r\n** CYPC weak inhibitors\r\n** CYPA non-sensitive substrates\r\n** CYPA weak inhibitors\r\n* These agents may be permitted if discontinuation is not feasible and no acceptable alternatives are available as determined by the treating physician; however, caution should be used; consider monitoring with labs or drug levels or by symptoms and consider dose adjustments of the medication
Participants receiving any medications, substances, or foods (i.e., grapefruit juice) listed below are ineligible:\r\n* Prescription or non-prescription drugs or other products known to be sensitive CYPA substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued prior to study start and withheld throughout the study until  weeks after the last dose of study drug; sensitive substrates of CYPC, CYPC, CYPC, or substrates of these enzymes with narrow therapeutic range\r\n* Inhibitors or substrates of P-glycoprotein (P-gp)
Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of CYPA, sensitive CYPA substrates and CYPA substrates with a narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as an antiemetic is prohibited due to early drug interaction data demonstrating increased exposure to AZD; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A) inhibitors such as atorvastatin is prohibited
Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYPA substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued  weeks prior to Day  of dosing and withheld throughout the study until  weeks after the last dose of study drug; co-administration of aprepitant or fosaprepitant during this study is prohibited; the use of sensitive substrates of CYPA, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this study; transporter studies (in vitro) have shown that AZD is an inhibitor of breast cancer resistance protein (BCRP); herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications  days prior to first dose of study treatment
Any chronic therapy or use of food supplements that are strong CYPA/ inducers or inhibitors or sensitive substrates of CYPA or CYPD with a narrow therapeutic window Abiraterone-Specific Exclusion Criteria:
Rx or non-Rx drugs or other products known to be sensitive BCRP or OAT substrates or to be potent inhibitors/inducers of CYPA, which cannot be discontinued  weeks prior to Day  of dosing and withheld throughout the study until  weeks after the last dose of AZD.
Concurrent administration of strong inducers and inhibitors of CYPA enzyme or CYPA substrates with narrow therapeutic window
Co-administration of CYPA ligands that serve as substrates or induce or inhibit the enzyme.
Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P family , subfamily A, polypeptide  (CYPA) substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued two weeks prior (alternatively  half lives if T/ is known) prior to day  of dosing and withheld throughout the study until  weeks after the last dose of study drug\r\n* NOTE: co-administration of aprepitant or fosaprepitant during this study is prohibited\r\n* Note: individual drugs exerting CYP interactions may be continued on a case by case basis if felt essential for patient management, after discussions and discretion of the treating physician\r\n* The preferred azole anti-fungal medication is fluconazole (alternatively posaconazole) which can be given during treatment with AZD at the treating physicians discretion, however with dose reductions of AZD by -% (i.e. from AZD mg to  or mg)
Patient has had prescription or non-prescription drugs or other products (ie, grapefruit juice) known to be moderate to strong inhibitors or inducers of CYPA, which cannot be discontinued  days before day  of dosing and withheld throughout the study until  days after the last dose of AZD; co-administration of aprepitant and fosaprepitant during this study is prohibited; co-treatment with weak inhibitors of CYPA is allowed
Unable or unwilling to discontinue use of any sensitive CYPA substrates and CYPA substrates with a narrow therapeutic window
Patient has had prescription or non-prescription drugs or other products (i.e., grapefruit juice) known to be sensitive to cytochrome P, family , subfamily A, polypeptide  (CYPA) substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYPA, which cannot be discontinued  weeks before day  of dosing and withheld throughout the study until  weeks after the last dose of study drug
Use of CYPA inhibitors or inducers and CYPD substrates must be discontinued prior to study entry
Inability to discontinue a prescription or non-prescription drugs or other products known to be metabolized by cytochrome P, family , subfamily A, polypeptide  (CYPA), or to inhibit or induce CYPA prior to day  of dosing and to withhold throughout the study until  weeks after the last dose of study medication; medications of particular concern are the following inhibitors of CYPA: azole antifungals (ketoconazole itraconazole, fluconazole and voriconazole), macrolide antibiotics (erythromycin, clarithromycin), cimetidine, aprepitant, human immunodeficiency virus (HIV) protease inhibitors, nefazodone and the following inducers of CYPA: phenytoin, barbiturates and rifampicin; substrates of CYPA include statins (lovastatin, simvastatin, atorvastatin), midazolam, terfenadine, astemizole, and cisapride
Patient has had prescription or non-prescription drugs or other products known to be sensitive to CYPA substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued  weeks prior to day  of dosing and withheld throughout the study until  weeks after the last dose of study drug; co-administration of aprepitant or fosaprepitant during this study is prohibited; the use of sensitive substrates of CYPA, such as atorvastatin, simvastatin and lovastatin, is also prohibited in this study
Patient has had a prescription or non-prescription drugs or other products known to be sensitive to CYPA substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued  weeks prior to day - of dosing and withheld throughout the study until  weeks after the last dose of study drug. Co-administration of aprepitant or fosaprepitant during this study is prohibited.
OATPB/ substrates
Patients currently receiving medications or herbal supplements of the classes below are ineligible; patients are eligible if they stop use of these compounds at least  week prior to receiving any treatment on this protocol\r\n* Potent inhibitors or inducers of CYPA / (CYPA inhibitors such as ketoconazole and clarithromycin are not allowed  days prior to the first dose of navitoclax and during navitoclax administration)\r\n* Strong or moderate inhibitors of Pgp or BRCP \r\n* Sensitive substrates of CYPC (i.e. phenytoin and warfarin)\r\n* Substrates of certain drug transporters (OATPB, OATPB, MATE or MATEK)
Patients must not be taking, nor plan to take while on protocol treatment and for  days post the last dose of study treatment, drugs, herbal supplements or foods that are known to be strong/moderate CYPA substrates
Patients must not be taking, nor plan to take while on protocol treatment and for  days after the last dose of study treatment, drugs, herbal supplements or foods that are known to be strong/moderate CYPA or CYPD substrates
Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive cytochrome P family , subfamily A, polypeptide  (CYPA) substrates, CYPA substrates with a narrow therapeutic index, moderate to potent inhibitors/inducers of CYPA; patients would be eligible if the medications can be discontinued two weeks prior to day  of dosing and withheld throughout the study until  weeks after the last dose of study medication
Patients who are currently receiving treatment (within  days prior to starting study treatment) with strong and moderate inhibitors or inducers of CYPA/, substrates of CYPA/ with a narrow therapeutic index or Herbal preparations/medications (Refer to Section . and Appendix ) Inclusion Criteria Exceptions for Phase Ib Dose Expansion patients: Dose Expansion part of the study has  groups, following are the Inclusion Criteria exceptions for these  groups
Sensitive CYPA/ substrates or CYPA/ substrates with narrow therapeutic index (NTI)
Sensitive CYPD substrates or CYPD substrates with NTI
Selected dual substrates of CYPA/ and CYPD
Selected dual substrates of OATP and CYP
Selected dual substrates of CYPA/ and P-gp
Prescription or non-prescription drugs or other products known to be sensitive to CYPA substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYPA which cannot be discontinued two weeks prior to Day  of dosing and withheld throughout the study until  weeks after the last dose of study drug.
Patients who require the following treatments moderate to strong CYPA inhibitors; any substrates of CYPA/ with a narrow therapeutic index
Medi+AZD Cohort only: received any potent and moderate cytochrome CYPA inhibitors, potent and moderate CYPA inducers, P-gp substrates, BCRP substrates, sensitive CYPB substrates, warfarin and coumarin derivatives, or herbal supplements within  days of the first dose of study treatment
Patients who are currently receiving treatment (that cannot be discontinued at least  week prior to the initiation of the study) with agents that are known to be any of the following: strong inducers or inhibitors of CYPA/; sensitive substrates of CYPA; substrates of CYPA/ or CYPC with a narrow therapeutic index.
Receiving medications that are moderate or strong inhibitors or inducers of CYPA or that are sensitive substrate or substrates with a narrow therapeutic index of CYPA, CYPD, or CYPC (see Appendix D)
Patients taking substrates, inhibitors, or inducers of CYPA should be encouraged to switch to alternative drugs whenever possible
Concomitant treatment with strong inhibitors or inducers of CYPA, CYPA or CYPA or sensitive substrates with narrow therapeutic index (TI) of CYPA, CYPC and CYPC within  days prior to enrollment and during the study unless there was an emergent or life-threatening medical condition that required it.
Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive cytochrome P, family , subfamily A, polypeptide  (CYPA) substrates, CYPA substrates with a narrow therapeutic index, moderate to potent inhibitors/inducers of CYPA; patients would be eligible if the medications can be discontinued two weeks prior to day  of dosing and withheld throughout the study until  weeks after the last dose of study medication
Subject has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYPA substrates
Patients may not be on drugs known to be moderate or potent inhibitors/inducers of CYPA, sensitive substrates of CYPA, or substrates of CYPA with narrow therapeutic windows
Participants who must receive CYPC inhibitors, substrates and inducers, strong CYPA inducers, or OATPB/ substrates while on study. These must be discontinued  days (inhibitors and substrates) or  days (inducers) prior to start of study medication
Use with caution:\r\n* CYPC non-sensitive substrates with a narrow therapeutic window and weak inhibitors are permitted if no acceptable alternatives are available as determined by the treating physician; however, caution should be used; consider monitoring with labs or drug levels and dose adjustments of the medication if feasible; other non-sensitive substrates are allowed on study\r\n* CYPA/ sensitive substrates and any non-sensitive substrates with a narrow therapeutic window and weak inhibitors are permitted if no acceptable alternatives are available as determined by the treating physician; however, caution should be used; consider monitoring with labs or drug levels and dose adjustments of the medication if feasible; other non-sensitive substrates are allowed on study\r\n* CYPD inducers, moderate/strong inhibitors or sensitive substrates are permitted if no acceptable alternatives are available; however, caution should be used; other non-sensitive substrates or weak inhibitors of CYPD are allowed on study
Patients who are currently receiving treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with WNT:\r\n* Strong inhibitors or inducers of cytochrome P, subfamily IIIA, polypeptide / (CYPA/)\r\n* CYPA/ substrates with narrow therapeutic index\r\n* Known to prolong the QT interval and are also CYPA/ substrates
Patients taking substrates, inhibitors and inducers of CYPA should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with irinotecan
Clinical requirement for medications that are concurrent inducers or inhibitors of CYPA; CYPA substrates are allowed
Inability to discontinue drugs that are strong cytochrome P A (CYPA) or P A (CYPA), cytochrome P C (CYPC), and cytochrome P C (CYP C) inhibitors and/or inducers; and substrates of CYP A/ or CYPA that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration
Caution should be exercised when inhibitors or substrates of P-glycoprotein (P-gP), substrates of cytochrome P family  subfamily A member  (CYPA) with a narrow therapeutic range, sensitive substrates of cytochrome P family  subfamily C member  (CYPC) or CYPC substrates with a narrow therapeutic range are administered with AZD
Subject has had prescription or non-prescription drugs or other products known to be sensitive cytochrome P family  subfamily A member  (CYPA) substrates or CYPA substrates with a narrow therapeutic index, or to be moderate to strong inhibitors / inducers of CYPA which cannot be discontinued two weeks prior to day  of dosing and withheld throughout the study until  weeks after the last dose of study drug; co-administration of aprepitant or fosaprepitant during this study is prohibited
Patients who are taking medications that may alter the metabolism of zolpidem; this includes strong CYPA inhibitors or inducers or CYPA substrates with a narrow therapeutic index