CHRONOS-4. Screening. Udført d. Graviditetstest Udført d. svar:

Transkript

1 Hæmatologisk Enhed 1 CPR: Patient ID Screening/ baseline Screening Sign: Informeret samtykke Udført d. Tjekke In- og eksklusionskriterier Medicinsk anamnese 1) Udført d. IVRS registrering 2) Udført d. Medicin status Udført d. AE registrering Udført d. B-symptomer Udført d. Objektiv undersøgelse Udført d. Virus blodprøver: HIV og Hepatitis B og C Udført d. Udført d. Udført d. Labka: Chronos4 (Screening) Udført d. Labka: CHRONOS1 Kemi (faste 11 timer før bl.pr) Udført d. Labka: CHRONOS1 Koag Udført d. Projektprøver (RH0062) Udført d. Graviditetstest Udført d. svar: EKG Udført d. MUGA Udført d. Urin-protein til kreatinin ratio UPCR (Spidsglas til 3011) Udført d. Urinstix Udført d. Knoglemarv Udført d. involvering J/N CT scan (hals, thorax, abdomen 3) Udført d. og pelvis) PET-CT (valgfri) 6) Udført d. Sende vævsbiopsi 4) Udført d. Oplæring i blodsukker apparat og måling samt introduktion til glukosedagbog Udført d. -14 Vitale værdier: Udført d. BT / p. Tp: Øre/Mund Højde: Vægt: P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\bayer _inhl\er\under udarbejdelse 1

2 Hæmatologisk Enhed 1 CPR: Patient ID Screening/ baseline Ved Mb. Waldenstrøm Sign: Serum protein elektroferese Udført d. Immunofixation Udført d. S-IgM Udført d. Plasmaviskositet 5) Udført d. positiv Ja/ Nej Beta-2-microglobulin Udført d. 1) Complete medical and surgical history including demographics, relevant medical history findings, concomitant illnesses, allergy history, prior surgeries, most recent histology of tumor, most recent staging and grading of tumor, history of anti-cancer treatments (including type of treatment, type of response, date and duration of response), and assessment of baseline toxicity. 2) IVRS/IWRS transaction to register the patient in the system will be at Screening. IVRS/IWRS randomization transaction will take place maximum 48 hours before the first dose (Cycle 1 Day 1). IVRS/IWRS transactions for medication dispensing will be on Day 1 of each cycle. 3) The first IV (and oral, if indicated, per Imaging Manual) contrast enhanced CT/MRI scans of neck, chest, abdomen and pelvis must be performed at Screening (including WM patients). Afdelingens standart procedure er CT-scan, men hvis der foreligger en MR-scan fra fx andet afsnit kan denne bruges 4) Tumor tissue collection will be mandatory for central pathology review. In addition, pre-treatment tumor tissue samples will be collected when available to investigate or identify biomarkers that may be predictive of copanlisib effects/efficacy in NHL and to contribute to better understanding the disease. Se yderligere s.107 I protokollen. 5) Skal kun tages ved symptomer på hyperviskositet. 6) If performed at baseline, PET-CT should be repeated after the 6th treatment cycle if a PD is not detected during the course of treatment and/or to confirm complete response (CR) or disease progression. P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\bayer _inhl\er\under udarbejdelse 2

3 Hæmatologisk Enhed 1 CPR: Patient ID Screening/ baseline Prohibited concomitant therapy: CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted within two weeks prior to start of study treatment until the SFU visit. Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit consumption is not permitted during the study. Anti-arrhythmic therapy other than beta blockers or digoxin. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Concomitant radiotherapy (it is assumed that radiation would be indicated only in case of progression, when the patient would come off study treatment anyway). Palliative radiotherapy is allowed (see Permitted concomitant therapy for details). Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed dose 7 days before performing the screening PET-CT and/or CT/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose before the screening. Patients may be using topical or inhaled corticosteroids. Short-term systemic corticosteroids above 15 mg prednisolone or equivalent will be allowed for the management of acute conditions (up to 7 days) and as premedication prior to rituximab infusion. The use of corticosteroids as antiemetics prior to copanlisib/placebo administration will not be allowed. Permitted concomitant therapy: Standard therapies for concurrent medical conditions. Treatment with non-conventional therapies (for example herbs or acupuncture), and vitamin/mineral supplements is acceptable provided that they do not interfere with the study endpoints, in the opinion of the Investigator. St John's Wort is not permitted. Bisphosphonates. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable. Close monitoring is recommended according to standard of care. If either of these values is above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until it is stable. Antiemetics: prophylactic anti-emetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of corticosteroids as antiemetics prior to study drug administration will be not allowed. Palliative and supportive care for the other disease-related symptoms and for toxicity associated with treatment will be offered to all patients in this trial. Patients may receive palliative and supportive care for any underlying illness. Palliative irradiation shall be permitted provided that: o In the opinion of the investigator, the patient does not have PD. P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\bayer _inhl\er\under udarbejdelse 3

4 Hæmatologisk Enhed 1 CPR: Patient ID Screening/ baseline o o The radiation field does not encompass a target lesion The radiation field does not encompass a lung field (to reduce the risk for pneumonitis). Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. Patients taking narrow therapeutic index medications should be monitored proactively, if these medications cannot be avoided. These medications may include quinidine and digoxin. Therapeutic drugs known to be substrates of Pgp and/or BCRP with narrow therapeutic index should be used with caution and patients monitored for any sign of toxicity. Furthermore, sensitive substrates of the renal drug transporter MATE2K (e.g. metformin) need to be used with caution. Metformin should be interrupted for 48 hours after receiving iodinated contrast media. Please see prescribing information for further information. Calcium channel blockers to control pre-existing hypertension. Non-dihydropyridine calcium channel blockers (Verapamil and diltiazem) should be avoided due to a potential CYP3A4 interaction. Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or equivalent will be allowed for the management of acute conditions (e.g. treatment of NIP). P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\bayer _inhl\er\under udarbejdelse 4

5 R-Benda + Copanlisib/ placebo CPR Cyklus 1-6 Patient ID Dato: Cyklus: (1 cyklus er 28 dage) CYKLUS 1 CYKLUS 2 CYKLUS 3 Dag: -1 til +2 (kun på dag ) I.V. Copanlisib/ placebo 1) SKAL GIVES FØRST. Dosis mg I.V. MabThera 375 mg/m I.V. Bendamustin 90 mg/m 2 -Efter afdelingens procedure Antimetika -Efter afdelingens procedure Medicinstatus 2) AE registrering version 4 3) Objektiv undersøgelse NYHA klassifikation 4) Performance status 5) CT-scan 6) af hals, thorax, abdomen samt pelvis (udføres + 7 dage) EKG 7) præ og post inf. copanlisib/ placebo MUGA 0 Labka: HEMA A1C 0 Labka: CHRONOS1 Hæmatologi Labka: Hæm + diff. 0 0 Labka:CHRONOS1 Kemi (F = faste 11 timer 0* 0* 0* 0 F 0* 0* 0* før bl.pr. * = uden triglyc.,total kolesterol & LDL) Labka: Lymfombehandling 0 Labka: CHRONOS1 Koagulation HCG, graviditets test. 0 0 Projektprøver (RHP062) 0 12PK 0 pk pk Værdier: BT., puls, Tp Vægt og urinstix 8) 0 0 Blodsukker (efter 8 timers faste) Blodsukker hjemmemålinger/ dagbog 9) QOL skema (FLymSI-18) e-pro Kun gældende for Morbus Waldenstrøm S-protein elektroferese/ Immunofixation/ S-IgM 10) 0 Plasma viskositet 11) Abnormal v baseline: 0 Ja Nej NA 0 behandlingsskema ver2 R-Benda + Copanlisib placebo.docx Side 1 af 5

6 R-Benda + Copanlisib/ placebo CPR Cyklus 1-6 Patient ID Dato: Cyklus: (1 cyklus er 28 dage) CYKLUS 4 CYKLUS 5 CYKLUS 6 Dag: -1 til +2 (kun på dag ) I.V. Copanlisib/ placebo 1) SKAL GIVES FØRST. Dosis mg I.V. MabThera 375 mg/m I.V. Bendamustin 90 mg/m 2 Gives efter afdelingens procedure Antimetika efter afdl. procedure Medicinstatus 2) AE registrering version 4 3) Objektiv undersøgelse NYHA klassifikation 4) Performance status 5) CT-scan 6) af hals, thorax, abdomen samt pelvis (udføres + 7 dage) 0 EKG 7) præ og post inf. copanlisib/ placebo 00 MUGA (udføres +7 dage) 0 Blodprøve HEMA A1C 0 Labka: CHRONOS1 Hæmatologi Labka: Hæm + diff Labka:CHRONOS1 Kemi (F = faste 11 timer før bl.pr. * = uden triglyc.,total kolesterol & LDL) 0 F 0 F Labka: Lymfombehandling Labka: CHRONOS1 Koagulation HCG, graviditetstest Projektprøver (RHP062) 0 pk 0 pk Værdier: BT., puls, Tp., vægt Vægt og urinstix 8) Blodsukker (efter 8 timers faste) Blodsukker hjemmemålinger/ dagbog 9) QOL skema (FLymSI-18) e-pro Kun gældende for Morbus Waldenstrøm S-protein elektroferese/ Immunofixation/ S-IgM 10) 0 Plasma viskositet 11) : Abnormal ved 0 baseline: Ja Nej NA behandlingsskema ver2 R-Benda + Copanlisib placebo.docx Side 2 af 5

7 R-Benda + Copanlisib/ placebo CPR Cyklus 1-6 Patient ID 1. Husk special drop grundet Copanlisibs gullige farve. Behandlingen skal gives i et saltvandsdrop over 1 time. For dosis modifikationer: se protokollem s. 54 pkt (protocol version 1.0) omhandler hematological toxicity, non-hematological toxicity, glucose increases and blood pressure increases. 2. Prohibited concomitant therapy: CYP3A4 inhibitors and inducers (see Appendix 16.1). Copanlisib is primarily metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted within two weeks prior to start of study treatment until the SFU visit. Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit consumption is not permitted during the study. Anti-arrhythmic therapy other than beta blockers or digoxin. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Concomitant radiotherapy (it is assumed that radiation would be indicated only in case of progression, when the patient would come off study treatment anyway). Palliative radiotherapy is allowed (see Permitted concomitant therapy for details). Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed. Patients may be using topical or inhaled corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before performing the screening PET-CT and/or CT/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the IC. The use of corticosteroids as antiemetics prior to copanlisib/placebo administration will not be allowed. Permitted concomitant therapy Standard therapies for concurrent medical conditions. Treatment with non-conventional therapies (for example herbs or acupuncture), and vitamin/mineral supplements is acceptable provided that they do not interfere with the study endpoints, in the opinion of the Investigator. St John's Wort is not permitted. Bisphosphonates. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable. Close monitoring is recommended according to standard of care. If either of these values is above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until it is stable. Antiemetics: prophylactic anti-emetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of corticosteroids as antiemetics prior to study drug administration will be not allowed. Palliative and supportive care for the other disease-related symptoms and for toxicity associated with treatment will be offered to all patients in this trial. Patients may receive palliative and supportive care for any underlying illness. Palliative irradiation shall be permitted provided that: In the opinion of the investigator, the patient does not have PD. behandlingsskema ver2 R-Benda + Copanlisib placebo.docx Side 3 af 5

8 R-Benda + Copanlisib/ placebo CPR Cyklus 1-6 Patient ID The radiation field does not encompass a target lesion The radiation field does not encompass a lung field (to reduce the risk for pneumonitis). Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. Patients taking narrow therapeutic index medications should be monitored proactively, if these medications cannot be avoided. These medications may include quinidine and digoxin. Therapeutic drugs known to be substrates of P-gp and/or BCRP with narrow therapeutic index should be used with caution and patients monitored for any sign of toxicity. Furthermore, sensitive substrates of the renal drug transporter MATE2K (e.g. metformin) need to be used with caution (see Appendix 16.2). Metformin should be interrupted for 48 hours after receiving iodinated contrast media. Please see prescribing information for further information. Calcium channel blockers to control pre-existing hypertension. Non-dihydropyridine calcium channel blockers (Verapamil and diltiazem) should be avoided due to a potential CYP3A4 interaction. Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or equivalent will be allowed for the management of acute conditions (e.g. treatment of NIP) and as premedication prior to rituximab infusion. 3. The investigator has to record on the respective CRF pages all adverse events occurring in the period that starts with the signing of the informed consent and will end in general with the SFU visit days after the last dose of study drug. During the active follow-up period, AEs and SAEs assessed as related to study procedures by the investigator will be reported. AE pages of the ecrf and the SAE form should be completed in the usual manner and forwarded to the applicable sponsor s GPV department behandlingsskema ver2 R-Benda + Copanlisib placebo.docx Side 4 af 5

9 R-Benda + Copanlisib/ placebo CPR Cyklus 1-6 Patient ID 6. CT-scans udføres: år 1+2 hv. 12 uge år hv. 24 uge Det er ikke nødvendigt at udføre CT-scan i forbindelse med EOT (fx ved PD) hvis scanningen er under 4 uger gammel. Hvis PET/CT er udført ved baseline, bør PET-CT gentages efter 6. cyklus, hvis PD ikke registreres i løbet af behandlingen og / eller for at bekræfte komplet respons (CR) eller sygdomsprogression. PET/CT skal bestilles som fusioneret. 7. EKG skal tages hv. 3 cyklus og max 2 timer før samt max 2 timer efter infusion af copanlisib/ placebo. 8. Stixes for : HgB, leukocytter, glukose, ketoner, bilirubin, protein og Ph. 9. ALLE patienter (både diabetespatienter og ikke-diabetiske patienter), der oplever vedvarende BS > 13.9 mmol/l eller har behov for insulin post-infusion vil blive bedt om at kontrollere blodsukkeret der hjemme mindst 3 gange dagligt i mindst 72 timer efter starten af infusion. Dette omfatter faste glukose (om morgenen før morgenmaden) og 2 yderligere målinger ca. 2 timer efter indtagelse af mad. Hvis der forsat efter de krævede 72 timer er BS på > 11.1 mmol/l (ikke-fastende), skal målingerne fortsætte indtil BS er under 11.1 mmol/l. Hvis der bliver givet insulin i forbindelse med behandlingen skal patienten observeres i 3 timer. Diabetes patienter skal desuden måle deres blodsukre som vanligt men bruge det blodsukker apparat der følger med studiet. 10. Skal tages i forbindelse med CT-scanningerne og med same interval dvs. år 1+2 hv. 12 uge år hv. 24 uge 11. S-viskositet skal kun tages hvis værdien var abnormal ved baseline. Hvis den var forhøjet ved baseline skal prøven tages hver tredje cyklus. 12. Obs. om patienten har underskrevet separat samtykke for Plasma for tumor genetics (tages KUN ved CYD1) PK= der skal tages PK prøver før og efter behandlingen iht. monitoreringsskemaet. Glas udleveres af KAT (5-8793). behandlingsskema ver2 R-Benda + Copanlisib placebo.docx Side 5 af 5

10 CPR R-CHOP + Copanlisib/ placebo Patient ID Dato: Cyklus: (1 cyklus er 21 dage) Cyklus 1 Cyklus 2 Cyklus 3 Dag: -1 til +2 (kun på dag 8-15) I.V. Copanlisib/ placebo 1) Dosis mg I.V. MabThera 375 mg/m I.V. Adriamycin-efter afdel. procedure I.V. Oncovin -efter afdel. procedure I.V. Cyklofosfamid -efter afdel. procedure Tabl. Prednison -efter afdel. procedure Medicinstatus 2) AE registrering version 4 3) Objektiv undersøgelse NYHA klassifikation 4) Performance status 5) CT-scan 6) af hals, thorax, abdomen samt pelvis (udføres + 7 dage) EKG 7) præ og post inf. copanlisib/ placebo MUGA 0 Labka: HEMA A1C 0 Labka:CHRONOS1 Hæmatologi Labka: Hæm + diff 0 0 Labka:CHRONOS1 Kemi (F = faste 11 timer før bl.pr. 0* 0* 0 F 0* 0* * = uden triglyc.,total kolesterol & LDL) Labka: Lymfombehandling 0 Labka:CHRONOS1 Koagulation HCG, graviditetstest 0 0 Projektprøver (RHP062) 0 12pk 0 pk 0 pk pk Værdier: BT., puls, Tp., Vægt og urinstix 8) 0 0 Blodsukker (efter 8 timers faste) Blodsukker hjemmemålinger/ dagbog 9) QOL skema (FLymSI-18) e-pro Kun gældende for Morbus Waldenstrøm S-protein elektroferese/ Immunofixation/S-IgM 10) Plasma viskositet 11) :Abnormal ved baseline: Ja Nej NA 0 behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx Side 1 af 5

11 CPR R-CHOP + Copanlisib/ placebo Patient ID Dato: Cyklus: (1 cyklus er 21 dage) Cyklus 4 Cyklus 5 Cyklus 6 Dag: -1 til +2 (kun på dag 8-15) I.V. Copanlisib/ placebo 1) Dosis mg I.V. MabThera 375 mg/m I.V. Adriamycin-efter afdel. procedure I.V. Oncovin -efter afdel. procedure I.V. Cyklofosfamid -efter afdel. procedure Tabl. Prednison -efter afdel. procedure Medicinstatus 2) AE registrering, version 4 3) Objektiv undersøgelse NYHA klassifikation 4) Performance status 5) CT-scan 6) af hals, thorax, abdomen samt pelvis (udføres + 7 dage) EKG 7) præ og post inf. copanlisib/ placebo 00 MUGA 0 Blodprøve: HEMA A1C 0 Labka: Hæm + diff Labka:CHRONOS1 Kemi (F = faste 11 timer før bl.pr. 0 F 0 F * = uden triglyc.,total kolesterol & LDL) Labka: Lymfombehandling Labka:CHRONOS1 Koagulation HCG, graviditetstest Projektprøver (RHP062) 0 pk 0 pk Værdier: BT., puls, Tp Vægt og urinstix 8) Blodsukker (efter 8 timers faste) Blodsukker hjemmemålinger/ dagbog 9) QOL skema (FLymSI-18) e-pro Kun gældende for Morbus Waldenstrøm 0 S-protein elektroferese/ Immunofixation/ S-IgM 10) 0 Plasma viskositet 11) : Abnormal ved baseline: Ja Nej NA 0 behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx Side 2 af 5

12 CPR R-CHOP + Copanlisib/ placebo Patient ID 1. Husk special drop grundet Copanlisibs gullige farve. Behandlingen skal gives i et saltvandsdrop over 1 time. For dosis modifikationer: se protokollem s. 54 pkt (protocol version 1.0) omhandler hematological toxicity, non-hematological toxicity, glucose increases and blood pressure increases. 2. Prohibited concomitant therapy: CYP3A4 inhibitors and inducers (see Appendix 16.1). Copanlisib is primarily metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted within two weeks prior to start of study treatment until the SFU visit. Grapefruit and grapefruit juice (CYP3A4 inhibitor), Seville oranges and star fruit consumption is not permitted during the study. Anti-arrhythmic therapy other than beta blockers or digoxin. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Concomitant radiotherapy (it is assumed that radiation would be indicated only in case of progression, when the patient would come off study treatment anyway). Palliative radiotherapy is allowed (see Permitted concomitant therapy for details). Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed. Patients may be using topical or inhaled corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days before performing the screening PET-CT and/or CT/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the IC. The use of corticosteroids as antiemetics prior to copanlisib/placebo administration will not be allowed. Permitted concomitant therapy Standard therapies for concurrent medical conditions. Treatment with non-conventional therapies (for example herbs or acupuncture), and vitamin/mineral supplements is acceptable provided that they do not interfere with the study endpoints, in the opinion of the Investigator. St John's Wort is not permitted. Bisphosphonates. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable. Close monitoring is recommended according to standard of care. If either of these values is above the therapeutic range, the doses should be modified and the assessments should be repeated weekly until it is stable. Antiemetics: prophylactic anti-emetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of corticosteroids as antiemetics prior to study drug administration will be not allowed. Palliative and supportive care for the other disease-related symptoms and for toxicity associated with treatment will be offered to all patients in this trial. Patients may receive palliative and supportive care for any underlying illness. Palliative irradiation shall be permitted provided that: In the opinion of the investigator, the patient does not have PD. The radiation field does not encompass a target lesion The radiation field does not encompass a lung field (to reduce the risk for pneumonitis). Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. Patients taking narrow therapeutic index medications should be monitored proactively, if these medications cannot be avoided. These medications may include quinidine and digoxin. behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx Side 3 af 5

13 CPR R-CHOP + Copanlisib/ placebo Patient ID Therapeutic drugs known to be substrates of P-gp and/or BCRP with narrow therapeutic index should be used with caution and patients monitored for any sign of toxicity. Furthermore, sensitive substrates of the renal drug transporter MATE2K (e.g. metformin) need to be used with caution (see Appendix 16.2). Metformin should be interrupted for 48 hours after receiving iodinated contrast media. Please see prescribing information for further information. Calcium channel blockers to control pre-existing hypertension. Non-dihydropyridine calcium channel blockers (Verapamil and diltiazem) should be avoided due to a potential CYP3A4 interaction. Short term (up to 7 days) systemic corticosteroids above 15 mg prednisone or equivalent will be allowed for the management of acute conditions (e.g. treatment of NIP) and as premedication prior to rituximab infusion. 3. The investigator has to record on the respective CRF pages all adverse events occurring in the period that starts with the signing of the informed consent and will end in general with the SFU visit days after the last dose of study drug. During the active follow-up period, AEs and SAEs assessed as related to study procedures by the investigator will be reported. AE pages of the ecrf and the SAE form should be completed in the usual manner and forwarded to the applicable sponsor s GPV department CT-scans udføres: år 1+2 hv. 12 uge år hv. 24 uge Det er ikke nødvendigt at udføre CT-scan i forbindelse med EOT (fx ved PD) hvis scanningen er under 4 uger gammel. Hvis PET/CT er udført ved baseline, bør PET-CT gentages efter 6. cyklus, hvis PD ikke registreres i løbet af behandlingen og / eller for at bekræfte komplet respons (CR) eller sygdomsprogression. PET/CT skal bestilles som fusioneret. behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx Side 4 af 5

14 CPR R-CHOP + Copanlisib/ placebo Patient ID 7. EKG skal tages hv. 3 cyklus og max 2 timer før samt max 2 timer efter infusion af copanlisib/ placebo. 8. Stixes for : HgB, leukocytter, glukose, ketoner, bilirubin, protein og Ph. 9. ALLE patienter (både diabetespatienter og ikke-diabetiske patienter), der oplever vedvarende BS > 13.9 mmol/l eller har behov for insulin post-infusion vil blive bedt om at kontrollere blodsukkeret der hjemme mindst 3 gange dagligt i mindst 72 timer efter starten af infusion. Dette omfatter faste glukose (om morgenen før morgenmaden) og 2 yderligere målinger ca. 2 timer efter indtagelse af mad. Hvis der forsat efter de krævede 72 timer er BS på > 11.1 mmol/l (ikke-fastende), skal målingerne fortsætte indtil BS er under 11.1 mmol/l. Hvis der bliver givet insulin i forbindelse med behandlingen skal patienten observeres i 3 timer. Diabetes patienter skal desuden måle deres blodsukre som vanligt men bruge det blodsukker apparat der følger med studiet. 10. Skal tages i forbindelse med CT-scanningerne og med same interval dvs. år 1+2 hv. 12 uge år hv. 24 uge 11. S-viskositet skal kun tages hvis værdien var abnormal ved baseline. Hvis den var forhøjet ved baseline skal prøven tages hver tredje cyklus. 12. Obs. om patienten har underskrevet separat samtykke for Plasma for tumor genetics (tages KUN ved CYD1) PK= der skal tages PK prøver før og efter behandlingen iht. monitoreringsskemaet. Glas udleveres af KAT (5-8793). behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx Side 5 af 5