Download Screening - Rigshospitalet

CHRONOS-4
Hæmatologisk Enhed 1
NAVN:
CPR:
Patient ID_________
Screening/ baseline
Screening
-28
Informeret samtykke
IVRS registrering
-7
Udført d.
Udført d.
Sign:
Udført d.
Tjekke In- og
eksklusionskriterier
Medicinsk anamnese
-14
1)
2)
Udført d.
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
.
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.
EKG
svar:
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
Udført d.
3)
og pelvis)
PET-CT (valgfri)
6)
Sende vævsbiopsi
Udført d.
4)
Udført d.
Oplæring i blodsukker apparat
og måling samt introduktion til
glukosedagbog
-14
Vitale værdier:
Udført d.
Udført d.
BT
/
Tp:
Højde:
p.
Øre/Mund
Vægt:
1
P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\BAYER-80-694617067_iNHL\Behandlingsskemaer\Under udarbejdelse
CHRONOS-4
Hæmatologisk Enhed 1
NAVN:
CPR:
Patient ID_________
Screening/ baseline
Ved Mb. Waldenstrøm
-28
-14
Serum protein elektroferese
Udført d.
Immunofixation
Udført d.
S-IgM
-7
Sign:
Udført d.
Plasmaviskositet
5)
Beta-2-microglobulin
Udført d.
positiv Ja/ Nej
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.
2
P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\BAYER-80-694617067_iNHL\Behandlingsskemaer\Under udarbejdelse
CHRONOS-4
Hæmatologisk Enhed 1
NAVN:
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.
3
P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\BAYER-80-694617067_iNHL\Behandlingsskemaer\Under udarbejdelse
CHRONOS-4
Hæmatologisk Enhed 1
NAVN:
CPR:
Patient ID_________
Screening/ baseline
o The radiation field does not encompass a target lesion
o 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).
4
P:\FIN\Lukkede Mapper\4241\Enhed 1 lymfomer\BAYER-80-694617067_iNHL\Behandlingsskemaer\Under udarbejdelse
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
Behandlingsskema
R-Benda + Copanlisib/ placebo
CHRONOS-4
Patient ID______
Cyklus 1-6
Dato:
Cyklus: (1 cyklus er 28 dage)
CYKLUS 1
Dag: -1 til +2 (kun på dag 8-15-22)
1
2
4
CYKLUS 2
8
15
0
0
22
1
2
8
15
0
0
CYKLUS 3
22
1
2
8
15
0
0
22
1)
I.V. Copanlisib/ placebo
SKAL GIVES FØRST. Dosis________mg
0
2
I.V. MabThera 375 mg/m
0
0
0
0
0
2
I.V. Bendamustin 90 mg/m
-Efter afdelingens procedure
Antimetika
-Efter afdelingens procedure
2)
Medicinstatus
AE registrering version 4
0
3)
Objektiv undersøgelse
NYHA klassifikation
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4)
0
0
0
0
0
0
0
0
0
0
0
0
5)
0
0
0
0
0
0
0
0
0
0
0
0
Performance status
6)
CT-scan af hals, thorax, abdomen
samt pelvis (udføres + 7 dage)
7)
EKG præ og post inf. copanlisib/
placebo
MUGA
0
00
00
0
Labka: HEMA A1C
0
Labka: CHRONOS1 Hæmatologi
0
Labka: Hæm + diff.
Labka:CHRONOS1 Kemi (F = faste 11 timer
0
0
0
0
0
0
0
0*
før bl.pr. * = uden triglyc.,total kolesterol & LDL)
0*
0*
F
0
0*
0*
0*
Labka: Lymfombehandling
0
Labka: CHRONOS1 Koagulation
HCG, graviditets test.
Projektprøver (RHP062)
0
Værdier: BT., puls, Tp.
8)
Vægt og urinstix
Blodsukker (efter 8 timers faste)
Blodsukker hjemmemålinger/ dagbog
0
012PK
0pk
0
0
0
0
0
0
0
9)
QOL skema (FLymSI-18) e-PRO
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0pk
0
0
0
0
0
0
0
0
0
0
0
Kun gældende for Morbus Waldenstrøm
S-protein elektroferese/
10)
Immunofixation/ S-IgM
11)
Plasma viskositet Abnormal v baseline:
Ja___ Nej___ NA___
0
0
P:\FIN\Lukkede Mapper\4241\Hjemmesiden\Protokoller og diverse skemaer til hjemmesiden\Enhed I\Lymfomer\Aktive\CHRONOS4\XO
behandlingsskema ver2 R-Benda + Copanlisib placebo.docx
Side 1 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
Behandlingsskema
R-Benda + Copanlisib/ placebo
CHRONOS-4
Patient ID______
Cyklus 1-6
Dato:
Cyklus: (1 cyklus er 28 dage)
CYKLUS 4
Dag: -1 til +2 (kun på dag 8-15-22)
1
2
CYKLUS 5
8
15
0
0
22
1
2
8
15
0
0
CYKLUS 6
22
1
2
8
1
5
0
0
22
1)
I.V. Copanlisib/ placebo
SKAL GIVES FØRST. Dosis________mg
I.V. MabThera 375 mg/m
0
2
0
0
0
0
0
2
I.V. Bendamustin 90 mg/m
Gives efter afdelingens procedure
0
0
0
0
0
0
Antimetika efter afdl. procedure
Medicinstatus
2)
AE registrering version 4
3)
Objektiv undersøgelse
4)
NYHA klassifikation
5)
Performance status
6)
CT-scan af hals, thorax, abdomen
samt pelvis (udføres + 7 dage)
7)
EKG præ og post inf. copanlisib/
placebo
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
00
MUGA (udføres +7 dage)
0
Blodprøve HEMA A1C
0
Labka: CHRONOS1 Hæmatologi
Labka: Hæm + diff.
0
Labka:CHRONOS1 Kemi (F = faste 11 timer
før bl.pr. * = uden triglyc.,total kolesterol & LDL)
Labka: Lymfombehandling
Labka: CHRONOS1 Koagulation
HCG, graviditetstest
Projektprøver (RHP062)
Værdier: BT., puls, Tp., vægt
Vægt og urinstix
9)
0
F
0
0
0
0
0
0
0
0
0
0
0
0
0
0pk
0
0
0
0
0
0
0
0
0pk
0
0
0
0
0
0
0
0
F
0
0
Blodsukker (efter 8 timers faste)
QOL skema (FLymSI-18) e-PRO
0
0
0
0
8)
Blodsukker hjemmemålinger/ dagbog
0
0
0
0
0
0
0
0
0
0
Kun gældende for Morbus Waldenstrøm
S-protein elektroferese/
10)
Immunofixation/ S-IgM
11)
Plasma viskositet : Abnormal ved
baseline: Ja___ Nej___ NA___
0
0
P:\FIN\Lukkede Mapper\4241\Hjemmesiden\Protokoller og diverse skemaer til hjemmesiden\Enhed I\Lymfomer\Aktive\CHRONOS4\XO
behandlingsskema ver2 R-Benda + Copanlisib placebo.docx
Side 2 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
1.
CHRONOS-4
Cyklus 1-6
Behandlingsskema
R-Benda + Copanlisib/ placebo
Patient ID______
Husk special drop grundet Copanlisibs gullige farve.
Behandlingen skal gives i et saltvandsdrop over 1 time.
For dosis modifikationer: se protokollem s. 54 pkt.7.4.1 (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.
P:\FIN\Lukkede Mapper\4241\Hjemmesiden\Protokoller og diverse skemaer til hjemmesiden\Enhed I\Lymfomer\Aktive\CHRONOS4\XO
behandlingsskema ver2 R-Benda + Copanlisib placebo.docx
Side 3 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR





3.
CHRONOS-4
Cyklus 1-6
Behandlingsskema
R-Benda + Copanlisib/ placebo
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.
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 30-35 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.
4.
5.
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behandlingsskema ver2 R-Benda + Copanlisib placebo.docx
Side 4 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
6.
CHRONOS-4
Cyklus 1-6
Behandlingsskema
R-Benda + Copanlisib/ placebo
Patient ID______
CT-scans udføres:
 år 1+2 hv. 12 uge
 år 3+4+5 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.
8.
EKG skal tages hv. 3 cyklus og max 2 timer før samt max 2 timer efter infusion af copanlisib/ placebo.
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 3+4+5 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).
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behandlingsskema ver2 R-Benda + Copanlisib placebo.docx
Side 5 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
Behandlingsskema
R-CHOP + Copanlisib/ placebo
CHRONOS-4
Patient ID______
Dato:
Cyklus: (1 cyklus er 21 dage)
Cyklus 1
Dag: -1 til +2 (kun på dag 8-15)
1
1)
I.V. Copanlisib/ placebo Dosis_______mg
2
4
0
Cyklus 2
8
15
0
1
2
0
8
Cyklus 3
15
0
1
2
0
0
0
0
I.V. Adriamycin-efter afdel. procedure
0
0
0
I.V. Oncovin -efter afdel. procedure
0
0
0
I.V. Cyklofosfamid -efter afdel. procedure
0
0
0
Tabl. Prednison -efter afdel. procedure
0
0
0
2)
AE registrering version 4
3)
15
0
I.V. MabThera 375 mg/m2
Medicinstatus
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Objektiv undersøgelse
4)
0
0
0
0
0
0
0
0
0
5)
0
0
0
0
0
0
0
0
0
0
0
NYHA klassifikation
Performance status
6)
CT-scan af hals, thorax, abdomen samt pelvis
(udføres + 7 dage)
7)
EKG præ og post inf. copanlisib/ placebo
00
00
MUGA
0
Labka: HEMA A1C
0
Labka:CHRONOS1 Hæmatologi
0
Labka: Hæm + diff
Labka:CHRONOS1 Kemi (F = faste 11 timer før bl.pr.
0*
* = uden triglyc.,total kolesterol & LDL)
0
0*
0
F
0
0
0*
0
0*
Labka: Lymfombehandling
0
Labka:CHRONOS1 Koagulation
HCG, graviditetstest
Projektprøver (RHP062)
0
012pk
Værdier: BT., puls, Tp.,
Vægt og urinstix
0pk
0
0pk
0
0
0
0
0
0
0
8)
0
0
0
0
0
Blodsukker (efter 8 timers faste)
Blodsukker hjemmemålinger/ dagbog
0
0
0
9)
0
QOL skema (FLymSI-18) e-PRO
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0pk
0
0
0
0
0
0
0
Kun gældende for Morbus Waldenstrøm
S-protein elektroferese/ Immunofixation/S-IgM
10)
11)
Plasma viskositet :Abnormal ved baseline:
Ja___ Nej___ NA___
0
P:\FIN\Lukkede Mapper\4241\Hjemmesiden\Protokoller og diverse skemaer til hjemmesiden\Enhed I\Lymfomer\Aktive\CHRONOS4\XO
behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx
Side 1 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
Behandlingsskema
R-CHOP + Copanlisib/ placebo
CHRONOS-4
Patient ID______
Dato:
Cyklus: (1 cyklus er 21 dage)
Cyklus 4
Dag: -1 til +2 (kun på dag 8-15)
1
1)
I.V. Copanlisib/ placebo Dosis _________ mg
2
0
8
Cyklus 5
15
0
1
2
0
8
Cyklus 6
15
0
1
2
0
0
0
0
I.V. Adriamycin-efter afdel. procedure
0
0
0
I.V. Oncovin -efter afdel. procedure
0
0
0
I.V. Cyklofosfamid -efter afdel. procedure
0
0
0
Tabl. Prednison -efter afdel. procedure
0
0
0
2)
AE registrering, version 4
3)
Objektiv undersøgelse
15
0
I.V. MabThera 375 mg/m2
Medicinstatus
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
NYHA klassifikation
4)
0
0
0
0
0
0
0
0
0
Performance status
5)
0
0
0
0
0
0
0
0
0
0
0
0pk
0
0
0
0
0
6)
CT-scan af hals, thorax, abdomen samt pelvis
(udføres + 7 dage)
0
7)
EKG 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
0
0
0
F
F
0
* = uden triglyc.,total kolesterol & LDL)
0
Labka: Lymfombehandling
0
0
0
Labka:CHRONOS1 Koagulation
HCG, graviditetstest.
Projektprøver (RHP062)
Værdier: BT., puls, Tp.
8)
Vægt og urinstix
Blodsukker (efter 8 timers faste)
9)
Blodsukker hjemmemålinger/ dagbog
QOL skema (FLymSI-18) e-PRO
0
0
0
0
0
0
0pk
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Kun gældende for Morbus Waldenstrøm
S-protein elektroferese/ Immunofixation/ S-IgM
10)
0
11)
Plasma viskositet :
Abnormal ved baseline:
Ja___ Nej___ NA___
0
P:\FIN\Lukkede Mapper\4241\Hjemmesiden\Protokoller og diverse skemaer til hjemmesiden\Enhed I\Lymfomer\Aktive\CHRONOS4\XO
behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx
Side 2 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
CHRONOS-4
Behandlingsskema
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.7.4.1 (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.
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Side 3 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR



3.
CHRONOS-4
Behandlingsskema
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.
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 30-35 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
4.
5.
6.
CT-scans udføres:
 år 1+2 hv. 12 uge
 år 3+4+5 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.
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behandlingsskema ver2 R-CHOP+ Copanlisib placebo.docx
Side 4 af 5
RIGSHOSPITALET
HÆMATOLOGISK KLINIK
NAVN:
CPR
CHRONOS-4
Behandlingsskema
R-CHOP + Copanlisib/ placebo
Patient ID______
7.
8.
EKG skal tages hv. 3 cyklus og max 2 timer før samt max 2 timer efter infusion af copanlisib/ placebo.
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 3+4+5 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).
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Side 5 af 5