Clinical trial NCT02516813
Conditions: Advanced Solid Tumors
Keywords: M3814 Advanced solid tumors DNA-PK Inhibitor Radiotherapy Chemotherapy
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2015-09-15; Completion date: 2021-11-19
Enrollment: 52 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
M3814 was an investigational drug that is being evaluated for the treatment of participants with locally advanced tumors. The main purposes of this study was to determine the safety, the tolerability and the efficacy of M3814 in combination with radiotherapy and in combination with chemoradiotherapy (Radiotherapy + cisplatin).

Detailed description:

Arms: arm 1: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative radiotherapy (RT) received 100 milligrams (mg) of M3814 as capsule orally once daily on fraction day (FD) 6 in combination with RT (3 Gray \[Gy\] x 10, 5 fractions per week \[F/W\]). arm 2: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). arm 3: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). arm 4: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 400 mg of M3814 as capsule orally once daily on FD 6 in combination with RT (3 \[Gy\] x 10, 5 F/W). arm 5: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 100 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). arm 6: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 200 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). arm 7: Participants with locally advanced disease (any tumor or metastases including lymphomas) localized in the head and neck region or thorax that was not amenable to surgical therapy, or with standard systemic therapy with an indication for palliative RT received 300 mg of M3814 as tablet orally once daily for 2 consecutive weeks in combination with RT (3 Gy x 10, 5 F/W). arm 8: Participants with local/locally advanced squamous cell carcinoma of the head and neck (SCCHN) received 50 mg of M3814 as capsule orally once daily on FD 6 in combination with fractionated RT (2 Gy x 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 milligrams per square meter (mg/m\^2) or weekly at a dose of 40 (mg/m\^2). arm 9: Participants with squamous cell carcinoma of the head and neck (SCCHN) received 100 mg of M3814 as tablet orally once daily for 7 consecutive weeks in combination with fractionated RT (2 Gy X 33 to 35 fractions; 5 F/W) and Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 (mg/m\^2). arm 10: Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 centimeters \[cm\] apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 100 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2. arm 11: Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 200 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2. arm 12: Participants with at least 2 (sub)cutaneous tumor/metastases of any type (at least 2 cm apart) with an indication for single high dose-palliative RT were included and received single oral dose of M3814 capsule at a dose of 400 mg on Day 2, prior 1.5 hours start of RT and a single high dose of RT (10-25 Gy) on Lesion 1 on Day 1 and on Lesion 2 on Day 2
Interventions: intervention 1: M3814 100 mg intervention 2: M3814 200 mg intervention 3: M3814 300 mg intervention 4: M3814 400 mg intervention 5: M3814 50 mg intervention 6: Fractionated RT intervention 7: Cisplatin
Intervention descriptions: intervention 1: Participants received 100 mg of M3814 as capsule or tablet orally once daily. intervention 2: Participants received 200 mg of M3814 as capsule or tablet orally once daily. intervention 3: Participants received 300 mg of M3814 as capsule or tablet orally once daily. intervention 4: Participants received 400 mg of M3814 as capsule or tablet orally once daily. intervention 5: Participants received 100 mg of M3814 as capsule orally once daily. intervention 6: Participants received fractionated palliative RT (3 Gray \[Gy\] \* 10 in Arm A and 2 Gy \* 33 to 35, 5 fractions per week \[F/W\]) in Arm B and received a single high dose of RT (10-25 Gy) capsule on Day 1 given on Lesion 1 and a single high dose of RT (10-25 Gy) on Day 2 given on Lesion 2 in ancillary CPoP part. intervention 7: Participants received Cisplatin twice at a dose of 100 mg/m\^2 or weekly at a dose of 40 mg/m\^2.

Protocol documents:
Prot_000.pdf: 


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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s u bsi diar y. C o p yri g ht © 2 0 1 9 b y  Merc k KG a A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts 
reser ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


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Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 3
Ta ble of I n -Te xt Ta bles ....................................................................................................... 8
Ta ble of I n -Te xt Fi g ures ...................................................................................................... 8
List of A b bre viati o ns ........................................................................................................... 9
1
S y n o psis ..............................................................................................1 4
2
S p o ns or, I n vesti gat ors a n d Trial A d mi nistrati ve Str uct ure ................ 5 6
2. 1
I n vesti gati o nal Sites............................................................................ 5 6
2. 2
C o or di nati n g I n vesti gat or ................................................................... 5 6
2. 3
K e y  Parties a n d Ser vice Pr o vi ders...................................................... 5 7
2. 4
Trial C o or di nati o n/ M o nit ori n g ........................................................... 5 7
2. 5
Safet y  M o nit ori n g C o m mittee............................................................ 5 8
3
Bac k gr o u n d I nf or mati o n ..................................................................... 5 8
............. 5 9
............. 5 9
3. 1. 2
F or m ulati o n De vel o p me nt .................................................................. 6 0
3. 2
Trial P o p ulati o n .................................................................................. 6 1
3. 3
Rati o nale f or Trial Desi g n a n d J ustificati o n of Starti n g D ose ............ 6 1
.............................. 6 2
3. 4
Rati o nale f or Ra di ot hera p y  D ose........................................................ 6 3
3. 5
Rati o nale f or Cis plati n D ose ...............................................................6 3
3. 6
K n o w n a n d P ote ntial Ris ks a n d Be nefits t o H u ma n S u bjects ............ 6 3
4
Trial O bjecti ves .................................................................................. 6 4
4. 1
Pri mar y O bjecti ves ............................................................................. 6 4
4. 2
Sec o n dar y  O bjecti ves ......................................................................... 6 4
........................................................ 6 5
5
I n vesti gati o nal Pla n ............................................................................ 6 6
5. 1
O verall Trial Desi g n a n d Pla n ............................................................ 6 6
5. 1. 1
D ose Escalati o n R ules ........................................................................7 1
5. 1. 2
Ta blet F or m ulati o n I ntr o d ucti o n, E val uati o n, a n d S M C Decisi o n 
Ma ki n g ................................................................................................7 4
5. 2
Disc ussi o n of Trial Desi g n ................................................................. 7 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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5. 2. 1
I ncl usi o n of S pecial P o p ulati o ns ................................ ........................7 6
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................7 6
5. 3. 1
I ncl usi o n Criteria ................................................................................ 7 6
5. 3. 2
E xcl usi o n Criteria ............................................................................... 7 8
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................ 8 0
5. 5
Criteria f or S u bject Wit h dra wal .......................................................... 8 0
5. 5. 1
Wit h dra wal fr o m Trial T hera p y.......................................................... 8 0
5. 5. 2
Wit h dra wal fr o m t he Trial .................................................................. 8 1
5. 6
Pre mat ure Ter mi nati o n of t he Trial .................................................... 8 1
5. 7
Defi niti o n of E n d of Trial ................................................................... 8 2
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Trial ..................................................................................................... 8 2
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct ........................ 8 2
6. 2
Descri pti o n of C o nc urre n t C he m ot hera py .......................................... 8 2
6. 3
D osa ge a n d A d mi nistrati o n ................................................................ 8 3
6. 3. 1
P hase Ia a n d I b Parts........................................................................... 8 3
6. 3. 2
A ncillar y  c P o P Part............................................................................. 8 8
6. 4
Assi g n me nt t o Treat me nt Gr o u ps ....................................................... 8 9
6. 5
N o ni n vesti gati o nal Me dici nal Pr o d ucts t o be Use d ............................ 8 9
6. 6
C o nc o mita nt Me dicati o ns a n d T hera pies ........................................... 8 9
6. 6. 1
Per mitte d Me dici nes ........................................................................... 8 9
6. 6. 2
Pr o hi bite d Me dici nes .......................................................................... 8 9
6. 6. 3
Ot her I nter ve nti o ns ............................................................................. 9 0
6. 6. 4
S pecial Preca uti o ns ............................................................................. 9 1
6. 6. 5
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns .............................................................................................9 1
6. 7
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct .... 9 2
6. 8
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct ...............................................................................9 2
6. 9
I n vesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y ............................. 9 2
6. 1 0
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce .........9 3
6. 1 1
Bli n di n g................................ ..............................................................9 3
6. 1 2
E mer ge nc y  U n bli n di n g.......................................................................9 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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6. 1 3
Treat me nt of O ver d ose .......................................................................9 4
6. 1 4
Me dical Care of S u bjects after E n d of Trial ....................................... 9 4
7
Trial Pr oce d ures a n d Assess me nts ...................................................... 9 4
7. 1
Sc he d ule of Assess me nts .................................................................... 9 4
7. 1. 1
Scree ni n g Peri o d ( Da y  -2 1 t o Da y  - 1)................................................ 9 4
7. 1. 2
Treat me nt Peri o d ................................................................................ 9 5
7. 1. 3
F oll o w -u p Peri o d ................................................................................ 9 9
7. 1. 4
Disc o nti n uati o n/ E n d of Trial ............................................................ 1 0 2
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics ............................ 1 0 2
7. 2. 1
De m o gra p hic Data ............................................................................ 1 0 3
7. 2. 2
T u m or Hist or y .................................................................................. 1 0 3
7. 2. 3
Me dical Hist or y  a n d Pre vi o us a n d C o nc o mita nt Me dicati o n........... 1 0 3
7. 2. 4
Vital Si g ns a n d P h y sical E xa mi nati o n.............................................. 1 0 3
7. 2. 5
C T or Ma g netic Res o na nce I ma gi n g Sca ns f or T u m or Assess me nt 1 0 4
7. 2. 6
Car diac Assess me nts ........................................................................ 1 0 4
7. 2. 7
Cli nical L a b orat or y Tests ................................................................. 1 0 4
7. 3
Efficac y  Assess me nts ....................................................................... 1 0 4
7. 3. 1
T u m or Res p o nse Assess me nt ........................................................... 1 0 4
7. 4
Assess me nt of Safet y ........................................................................ 1 0 5
7. 4. 1
A d verse E ve nts ................................................................................. 1 0 5
7. 4. 2
Pre g na nc y  a n d I n Uter o Dr u g E x p os ure........................................... 1 1 2
7. 4. 3
Cli nical L a b orat or y Assess me nts ..................................................... 1 1 2
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts........... 1 1 4
7. 5
P har mac o ki netics .............................................................................. 1 1 4
7. 5. 1
Sa m ple C ollecti o n .............................................................................1 1 4
7. 5. 2
P har mac o ki netic Calc ulati o ns ................................ ..........................1 1 5
.......................................................... 1 1 6
..........................................................1 1 6
..........................................................1 1 7
7. 7
Ot her Assess me nts ............................................................................1 1 8
8
Statistics ............................................................................................1 1 8
.................................................................................1 1 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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8. 2
Ra n d o mizati o n ..................................................................................1 2 1
8. 3
E n d p oi nts .......................................................................................... 1 2 1
8. 3. 1
Pri mar y  E n d p oi nts............................................................................ 1 2 1
8. 3. 2
Sec o n dar y  E n d p oi nts........................................................................ 1 2 2
...............................................................1 2 2
8. 4
A nal y sis Sets..................................................................................... 1 2 3
8. 5
Descri pti o n of Statistical A nal y ses ................................................... 1 2 4
8. 5. 1
Ge neral C o nsi derati o ns ..................................................................... 1 2 4
8. 5. 2
A nal y sis of Pri mar y E n d p oi nts......................................................... 1 2 5
8. 5. 3
A nal y sis of Sec o n dar y E n d p oi nts..................................................... 1 2 5
8. 5. 4
A nal y sis of Safety a n d Ot her E n d p oi nts ........................................... 1 2 6
..................................................... 1 2 7
8. 6
I nteri m A nalys is................................................................................ 1 2 7
9
Et hi cal a n d Re g ulat or y As pects ........................................................ 1 2 7
9. 1
Res p o nsi bilities of t he I n vesti gat or .................................................. 1 2 7
9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt ..................................... 1 2 8
9. 3
S u bject I de ntificati o n a n d Pri vac y .................................................... 1 2 9
9. 4
E mer ge nc y  Me dical S u p p ort a n d S u bject Car d................................ 1 2 9
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects ................... 1 3 0
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d ........ 1 3 0
9. 7
Healt h A ut h orities ............................................................................. 1 3 0
1 0
Trial Ma na ge me nt ............................................................................. 1 3 0
1 0. 1
Case Re p ort F or m Ha n dli n g .............................................................1 3 0
1 0. 2
S o urce Data a n d S u bject Files .......................................................... 1 3 1
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g................................................. 1 3 1
1 0. 4
M o nit ori n g, Q ualit y Ass ura nce a n d I ns pecti o n b y Healt h 
A ut h orities ........................................................................................ 1 3 2
1 0. 5
C ha n ges t o t he Cli nical Trial Pr ot oc ol .............................................. 1 3 2
1 0. 6
Cli nical Trial Re p ort a n d P u blicati o n P olic y .................................... 1 3 2
1 0. 6. 1
Cli nical Trial Re p ort .........................................................................1 3 2
1 0. 6. 2
P u blicati o n ........................................................................................1 3 3
1 1
Refere nces Cite d i n t he Te xt .............................................................1 3 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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1 2
A p pe n dices .......................................................................................1 3 5
A p pe n di x A:
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial.................... 1 3 5
Si g nat ure Pa ge – Pr ot oc ol L ea d ....................................................................................... 1 3 6
Si g nat ure Pa ge – C o or di nati n g I n vesti gat or.................................................................... 1 3 7
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 3 8
S p o ns or Res p o nsi ble Pers o ns n ot Na me d o n t he C o ver Pa ge ......................................... 1 3 9
A p pe n di x B:
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T v 1. 1) ....... 1 4 0
...................................................................... 1 4 5
A p pe n di x D:
O utli ne of I nte nsit y -m o d ulate d Ra di ot hera p y .................................. 1 4 7
A p pe n di x E:
C o ntrace pti ve G ui da nce a n d W o me n of C hil d beari n g P ote ntial ...... 1 4 8
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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T a ble of I n-Te xt T a bles
Ta ble 1 
Sc he d ule of Assess me nts – P hase Ia ( Ar m A): Ca ps ule C o h orts....... 2 7
Ta ble 2
Sc he d ule of Assess me nts – P hase Ia ( Ar m A): Ta blet C o h orts.......... 3 1
Ta ble 3
Sc he d ule of Assess me nts – First 3 S u bjects i n P hase I b ( Ar m A; 
N S C L C C o h ort) .................................................................................. 3 6
Ta ble 4
Sc he d ule of Assess me nts – P hase I b ( Ar m A; N S C L C C o h ort) ........ 4 0
Ta ble 5
Sc he d ule of Assess me nts – P hase Ia ( Ar m B; S C C H N C o h ort) ........ 4 3
Ta ble 6
Sc he d ule of Assess me nts – P hase I b ( Ar m B; S C C H N C o h ort) ........ 4 7
Ta ble 7
Sc he d ule of Assess me nts – A ncillar y  Cli nical Pr o of-of- Pri nci ple 
Part ...................................................................................................... 5 1
Ta ble 8
Ra di ot hera p y ( Al o ne) a n d M 3 8 1 4 + R T Sc he d ule f or t he 
A ncillar y  Cli nical Pr o of-of- Pri nci ple (c P o P) Part of t he Trial ........... 5 4
Ta ble 9
P har mac o ki netic a n d 
 Sa m pli n g Sc he d ule of 
M 3 8 1 4 d uri n g P hase
Ia, P hase I b, a n d t he A ncillar y c P o P Part of 
t he Trial...............................................................................................5 5
Ta ble 1 0
Trial A d mi nistrati ve Str uct ure ............................................................ 5 7
..6 2
Ta ble 1 2
D oses of M 3 8 1 4 i n t he A ncillar y  c P o P Part of t he Trial.................... 7 3
Ta ble 1 3
D ose M o dificati o ns f or M 3 8 1 4, Ra di ot hera p y, a n d Cis plati n 
D uri n g t he Trial ..................................................................................8 5
Ta ble 1 4
Pre d osi n g C o nsi derati o ns f or Cis plati n .............................................. 8 8
Ta ble 1 5
Re q uire d La b orat or y  Safet y Tests.................................................... 1 1 3
T a ble of I n-Te xt Fi g ures
Fi g ure 1
O ver vie w of Trial Desi g n wit h 5 Se g me nts ....................................... 6 7
Fi g ure 2
Sc he matic of Trial Desi g n .................................................................. 6 8
Fi g ure 3
Treat me nt O ver vie w ( P hase Ia Ar m A) .............................................. 6 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
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List of A b bre vi ati o ns
A D M E
A bs or pti o n, distri b uti o n, meta b olis m, a n d eli mi nati o n
A E
A d verse eve nt
A D R
A d verse dr u g reacti o n
A L L 
All su bjects (a nal ys is set)
A L T
Ala ni ne a mi n otra nsferase
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
A U C 0- ∞
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o e xtra p olate d t o i nfi nit y
A U C 0-t
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n
A U C τ
Area u n der t he c o nce ntrati o n-ti me c ur ve o ver t he d osi n g i nter val after m ulti ple 
d osi n g
B C R P
Breast ca ncer resista nce pr otei n
BI D
T wice dail y
B S A
B o d y s urface area
CI
C o nfi de nce i nter val
C L /f
Oral cleara nce
C L ss/f
Oral cleara nce at stea d y s tate
C N S
Ce ntral ner v o us s ys te m
c P o P
Cli nical p r o of-of- p ri nci ple
C R O
C o ntract researc h o r ga nizati o n
C R T
C he m ora di ot hera p y
C T
C o m p ute d t o m o gra p h y
C T C A E
C o m m o n ter mi n ol o g y criteria f or a d verse eve nts
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
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C O N F I D E N T I A L
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ct D N A
Circ ulati n g t u m or D N A
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
C Y P
C y t oc hr o me P 4 5 0
D E
D ose escalati o n (a nal ys is set)
D L T
D ose li miti n g t o xicit y
D N A -P K
De o x yri b o n ucleic aci d -de pe n de nt pr otei n ki nase
D S B
D o u ble- stra n d brea k
E C G
E lectr ocar di o gra m
E C O G P S
Easter n c o o perati ve o nc ol o g y  gr o u p perf or ma nce stat us
e C R F
Electr o nic case re p ort f or m
E O T
E n d of trial
E T T
Earl y treat me nt ter mi nati o n
F A S
F ull a nal ys is set
F D
Fracti o n d a y
FI M
First -i n-ma n
F T
Fee di n g t u be
F U
F oll o w -u p
F/ W
Fracti o ns per wee k
G C P
G o o d cli nical practice
G -C S F
Gra n ul oc y te-c ol o n y sti m ulati n g fact or
G y
Gra y  ( deri ve d u nit of i o nizi n g ra diati o n d ose)
H B V
He patitis B vir us
H C G
H u ma n c h ori o nic g o na d otr o pi n
H C V
He patitis C vir us
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 4 9
P K
P har mac o ki netic (s)
P PI
Pr ot o n p u m p i n hi bit or
P T D
P ost -treat me nt d a y
Q D
O nce dail y
Q Tc F
Fri dericia -c orrecte d Q T i nter val
R acc( A U C)
Acc u m ulati o n rati o f or area u n der t he c o nce ntrati o n-ti me c ur ve
R acc( C ma x)
Acc u m ulati o n rati o f or ma xi m u m c o nce ntrati o n
R E CI S T
Res p o nse eval uati o n criteria i n soli d tu m ors
R P 2 D
Rec o m me n de d P hase II d ose
R T
Ra di ot hera p y
S A E
Seri o us a d verse eve nt
S A F
Safet y  anal ys is set
S A P
Statistical anal y sis p la n
S C C H N
S q ua m o us cell carci n o ma hea d a n d nec k
S D
Sta n dar d de viati o n
S M C
Safet y  Mo nit ori n g C o m mittee 
S m P C
S u m mar y  of pr o d uct c haracteristics
S o C
Sta n dar d of C are
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
A p pare nt ter mi nal half -life
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
tma x
Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n
U L N
U p per li mit of n or mal
U S A
U nite d States of A merica
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 4 9
V z/f
A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase
V ss/f
A p pare nt v ol u me of distri b uti o n at stea d y state
W O C B P  
W o ma n of c hil d beari n g p ote ntial
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 4 9
o
( Ar m B) T o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h
c urati vel y i nte n de d c he m ora di ot hera p y ( C R T: 2 G y x 3 3 t o 3 5; 5 F/ W wit h 
c o nc urre nt cis plati n ) i n treat me nt-naï ve s u bjects wit h l ocal/l ocall y a d va nce d 
S C C H N .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
( Ar m A) T o e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h 
fracti o nate d R T ( 2 G y  x 33 ; 5 F/ W) i n treat me nt-naï ve s u bjects wit h S ta ge III A/ B 
n o n- s mall cell l u n g ca ncer ( N S C LC) n ot eli gi ble f or c o nc urre nt c he m ora diati o n
o
( Ar m B) T o e val uate t he safet y a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h C R T 
( 2 G y x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt c is plati n) i n s u bjects wit h treat me nt-naï ve
S C C H N .
Sec o n d ar y o bjecti ves:

P hase Ia ( d ose escalati o n): 
o
T o e val uate t he safet y pr ofile a n d t olera bility of M 3 8 1 4
i n c o m bi nati o n wit h R T 
( Ar m A) a n d C R T ( Ar m B)
o
T o e x pl ore t he a ntit u m or acti vit y of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A ) a n d 
C R T (Ar m B) .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
T o e x pl ore t he efficac y i n ter ms of o verall res p o nse rate, pr o gressi o n free s ur vi val 
( P F S) a n d o verall s ur vi val ( O S) of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) or i n 
c o m bi nati o n wit h C R T ( Ar m B), a n d l ocal/l ocal re gi o nal t u m or c o ntr ol ( Ar m B)

P hase Ia, P hase I b, a n d t he a ncillar y c P o P part of t he trial : T o assess t he p har mac o ki netics 
( P K) of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 4 9
Met h o d ol o g y: T his is a c o m bi ne d P hase I a/I b, o pe n la bel, d ose escalati o n a n d d ose e x pa nsi o n 
trial desi g ne d t o e x pl ore t he safety, t olera bilit y, P K a n d P D pr ofile, a n d cli nical acti vit y of 
M 3 8 1 4
i n c o m bi nati o n wit h R T / C R T, a n d t o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n 
c o m bi nati o n wit h R T / C R T. A n a ncillar y cP o P part of t he trial will be c o n d ucte d i n p arallel 
wit h t he P hase Ia/I b c ore trial t o e x pl ore t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n 
tar get e n ga ge me nt i n t u m or tiss ue.
I n t he P hase Ia part of t he trial, pre vi o usl y treate d s u bjects wit h l ocall y a d va nce d disease (a ny 
t u m or or metastas es i ncl u di n g l ym p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x t hat 
is n ot a me na ble t o s ur gical t hera p y or wit h sta n dar d s yste mic t hera p y wit h a n i n dicati o n f or 
palliati ve R T ( 3 0 G y  in 1 0 fracti o ns) will be i ncl u de d i n Ar m A. After t he first d ose le vel i n 
Ar m A has bee n c o m plete d, a sec o n d d ose escalati o n ar m ( Ar m B) will be i nitiate d i n 
treat me nt-naï ve s u bjects wit h S C C H N, w h o are eli gi ble f or fracti o nate d R T ( 6 6 t o 7 0 G y  in 
3 3 t o 3 5 fracti o ns) wit h c o nc urre nt cis plati n. T he d ose escalati o n of M 3 8 1 4
deter mi ne d b y t he 
Safet y  Mo nit ori n g C o m mittee ( S M C) will be g ui de d b y  the Ba ye sia n l o gistic m o del wit h 
o ver d ose c o ntr ol.
I n t he P hase I b part, eac h ar m fr o m P hase Ia will ha ve a n e x pa nsi o n c o h ort. After esta blis h me nt 
of R P 2 D i n Ar m A, s u bjects wit h treat me nt-naï ve S ta ge III A/ B N S C L C , n ot eli gi ble f or
s ur gical resecti o n or c o nc urre nt c he m ora diati o n, will be gi ve n 6 6 G y  i n 3 3 fracti o ns. T he d ose 
of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms of
P hase Ia. I n case a R P 2 D i n Ar m B has bee n esta blis he d bef ore a R P 2 D i n Ar m A, t he n t he 
e x pa nsi o n c o h ort f or Ar m A ca n be i nitiate d at t hat d ose. I n case a R P 2 D has bee n esta blis he d 
i n Ar m A o nl y , t he n t he first 3 s u bjects i n t he e x pa nsi o n c o h ort f or Ar m A will be treate d at
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 4 9
o ne d ose le vel bel o w t he R P 2 D. T he S M C will deter mi ne if it is safe t o escalate t he d ose . T he 
e x pa nsi o n c o h ort f or Ar m B will i ncl u de treat me nt-naï ve s u bjects wit h S C C H N, as s pecifie d 
i n P hase Ia, a n d will be gi ve n t he sa me C R T ( 6 6 t o 7 0 G y i n 3 3 t o 3 5 fracti o ns wit h c o nc urre nt 
cis plati n) i n c o m bi nati o n wit h M 3 8 1 4
at t he R P 2 D esta blis he d i n P hase Ia Ar m B.
I n t he a ncillar y c P o P part of t he trial , s u bjects wit h at least 2 (s u b)c uta ne o us t u m or/ metastases 
of a n y ty pe (at least 2 c m a part) wit h a n i n dicati o n for si n gle hi g h d ose palliati ve R T will be 
i ncl u de d. T he d ose of M 3 8 1 4
will be i n t he ra n ge of 1 0 0 t o 4 0 0 m g o nce dail y  (Q D ).
T he c urre nt trial i nitiall y starte d t o i n vesti gate M 3 8 1 4 b y  use of a p o w d er-i n-ca ps ule ( Pi C) 
f or m ulati o n. W hile
t he d ose escalati o n p hase of P hase Ia was o n g oi n g , a ne w 
 ta blet 
f or m ulati o n of M 3 8 1 4 beca me a vaila ble. T he
 ta blet will be i ntr o d uce d a n d e val uate d i n 
t his trial.
Scree ni n g p eri o d
After pr o vi di n g i nf or me d c o nse nt f or t he trial a n d t he p har mac o ge netic ( P G x) a nal ysis, t he 
eli gi bilit y of trial s u bjects will be esta blis he d acc or di n g t o t he pr ot oc ol -defi ne d incl usi o n a n d 
excl usi o n criteria d uri n g a ma xi m u m 2 1- da y  Scree ni n g Peri o d (scree ni n g a n d baseli ne 
e val uati o ns). O nce all scree ni n g pr oce d ures ha ve bee n c o m plete d a n d it has bee n c o nfir me d 
t hat a s u bject meets all t he eli gi bilit y criteria, t he s u bject will be e nr olle d i nt o t he trial a n d e nter 
t he treat me nt p eri o d. 
Tre at me nt p eri o ds
T hr o u g h o ut t he treat me nt p eri o d, s u bjects i n all c o h orts will atte n d re g ular trial visits f or 
d osi n g, safet y e val uati o ns a n d bl o o d sa m pli n g f or P K a n d P D.
P hase Ia 
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, s u bjects e nr olle d i n t he 
P hase Ia part of t he trial will recei ve treat me nt wit h a ca ps ule f or m ulati o n of M 3 8 1 4
at a 
starti n g d ose of 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or Ar m B, w hic h will be gi ve n 1. 5 h o urs
( ± 3 0 mi n utes) bef ore eac h R T fracti o n ( 3 G y ) f or u p t o 1 0 fracti o ns ( Ar m A) or 2 G y f or 3 3 t o 
3 5 fracti o ns ( Ar m B) .
I n b ot h ar ms, d ose escalati o n will c o nti n ue wit h t he M 3 8 1 4 
ca ps ule f or m ulati o n fr o m 
1 0 0 m g/ da y ( Ar m A) or 5 0 m g/ da y ( Ar m B) u p t o a ma xi m u m d ose of 8 0 0 m g/ da y u ntil o ne 
of t he f oll o wi n g st o p pi n g r ules a p pl y: a ma xi m u m n u m ber of 3 0 s u bjects are i ncl u de d, m ore 
t ha n t hree c o h orts are assi g ne d t o t he sa me d ose le vel or t he esti mate f or d ose li miti n g t o xicit y  
(D L T ) pr o ba bilit y  of t he M T D 
reac hes s ufficie nt precisi o n. It is a ntici pate d t hat u p t o 
3 0 e val ua ble s u bjects ( 1 0 c o h orts of 3 s u bjects) ma y  be nee de d i n eac h ar m i n or der t o 
deter mi ne t he M T D of M 3 8 1 4 .
T he ta blet will be i ntr o d uce d first i n P hase Ia Ar m A i n c o m bi nati o n wit h R T. S u bjects will 
recei ve t he ta blet at a starti n g d ose of 1 0 0 m g Q D . Safet y, t olera bilit y a n d e x p os ure data alrea d y 
ge nerate d wit h t he ca ps ule f or m ulati o n of M 3 8 1 4 i n c o m bi nati o n wit h R T will g ui de t he 
esta blis h me nt of t he R P 2 D wit h t he ta blet. I n ad diti o n, a n i ntra-i n di vi d ual c o m paris o n of 
M 3 8 1 4 P K bet wee n t he ta blet a n d ca ps ule will be perf or me d i n P hase Ia Ar m A. T hese P K 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 4 9

S h ort -ter m Safet y Foll o w -u p: A f oll o w-u p peri o d of 3 0 da y s after t he e n d of R T f or e val uati o n 
of safet y

M i d-ter m Safet y  Foll o w -u p: A safet y f oll o w-u p peri o d of 3 m o nt hs
after t he e n d of R T t o 
e val uate late si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

L o n g -ter m Safet y  F oll o w -u p : A safet y foll o w -u p peri o d u ntil 1 2 m o nt hs after e n d of R T t o 
e val uate late si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

S ur vi val F oll o w -u p : A f oll o w -u p peri o d t hat will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T / C R T.
A ncillar y  c P o P part of t he trial
A f oll ow- u p peri o d of 3 0 da y s after t he e n d of t he R T/ M 3 8 1 4
f or e val uati o n of safet y. S u bjects 
will be per mitte d t o recei ve a n y  i n dicate d t hera pe utic m o dalit y as s o o n as cli nicall y i n dicate d after 
Da y 1 0.
D ose esc al ati o n
M 3 8 1 4 d ose escalati o n will n ot pr ocee d t o t he ne xt d ose le vel u ntil all s u bjects ha ve c o m plete d t he 
D L T peri o d .
P hase Ia
A Ba y esia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose c o ntr ol will be use d t o assist 
t he S M C wit h d ose selecti o n d uri n g t he P has e Ia d ose escalati o n. C o h orts of 3 s u bjects eac h will 
be treate d at t he sa me d ose le vel ( ca ps ule starti n g d ose: 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or 
Ar m B ). T he m o del 
i nc or p orates pri or i nf or mati o n (fr o m n o n cli nical data) a n d o bser ve d 
i nf or mati o n fr o m eac h c o m plete d c o h ort (a n d data fr o m all pre vi o us c o h orts) t o pr o vi de a 
rec o m me n de d d ose f or t he ne xt c o h ort. A preselecte d set of acce pta ble d oses are c o nsi dere d b y  t he 
m o del, h o we ver d oses w hic h are n ot part of t he pres pecifie d set ma y  be c h ose n as well .T he m o del 
e ns ures t hat rec o m me n de d d oses c orres p o n d t o a pr o ba bilit y  of less t ha n 2 5 % t hat t he tr ue D L T  
rate is m ore t ha n 3 5 % i n Ar m A a n d 4 5 % i n Ar m B . D ose escalati o n will st o p i n eac h ar m as s o o n 
as t he first of t he f oll o wi n g st o p pin g r ules a p ply:  a ma xi m um of 3 0 s u bjects are i ncl u de d, m ore 
t ha n t hree c o h orts are assi g ne d t o t he sa me d ose le vel, or t he esti mate of D L T pr o ba bilit y  at t he 
M T D reac hes a s ufficie nt precisi o n .
P hase I b
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, treat me nt-naï ve s u bjects wit h 
S ta ge III A/ B N S C L C e nr olle d i n t he P hase I b part of t he trial ( Ar m A e x pa nsi o n c o h ort) will 
recei ve M 3 8 1 4 , t o be gi ve n 1. 5 h o ur s ( ± 3 0 mi n utes) bef ore eac h R T fr acti o n f or 3 3 fracti o ns. T he
d ose of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms 
of t he P hase Ia part of t he trial . 
T he d ose i n t he Ar m B e x pa nsi o n c o h ort will be t he deter mi ne d R P 2 D of M 3 8 1 4 fr o m P hase Ia, 
Ar m B a n d will be gi ve n t o s u bjects wit h treat me nt-naï ve S C C H N i n c o m bi nati o n wit h t he sa me 
C R T re gi me n as i n P hase Ia ( Ar m B).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 4 9
D oses of M 3 8 1 4
i n t he a ncill ar y c P o P p art of t he tri al
A ncillar y  c P o P part
T he si n gle d ose of M 3 8 1 4
t o be a d mi nistere d o n Da y  2 of the a ncillar y c P o P part of t he trial is 
fi xe d f or s uccessi ve c o h orts as s h o w n bel o w:
D ose s of M 3 8 1 4 i n t he a ncill ar y c P o P p art of t he tri al
D ose ( m g) a
N u m ber of s u bjects i ncl u de d b
1 0 0
3 
2 0 0
3
4 0 0
3
( > 1 0 0 / < 4 0 0) c
( 3)
c P o P = cli nical pr o of -of -pri nci ple; 
=
 P K = p har mac o ki netics; R P 2 D = rec o m me n de d P hase II d ose; 
S M C = Safet y M o nit ori n g C o m mittee .
a.
A d diti o nal c o h orts of M 3 8 1 4 ( 
 f or m ulati o n) ma y be i ntr o d uce d . T he starti n g d ose a n d s u bse q ue nt d ose le vels of 
M 3 8 1 4 (
f or m ulati o n) will be defi ne d b y t he S M C base d o n P K a n d safet y data ge nerate d i n o n g oi n g cli nical 
st u dies e val uati n g t he safet y, t olera bilit y, P K, a n d p har mac o d y na mics of M 3 8 1 4 (
f or m ulati o n).
b.  
A t t he R P 2 D a n a d diti o nal 2 s u bjects will be i ncl u de d ma ki n g 5 s u bjects at t he R P 2 D .
c.  
Ad diti o nal d oses mi g ht be o pe ne d u p o n S M C decisi o n .
Pl a n ne d n u m ber of s u bjects: U p t o 1 5 5 e val ua ble s u bjects will be e nr olle d i n t his trial: 
a p pr o xi matel y 7 8 e val ua ble s u bjects i n P hase Ia part; u p t o 5 4 e val ua ble s u bjects i n P hase I b 
d ose e x pa nsi o n part; a n d a p pr o xi matel y 23 s u bjects i n t he a ncillar y c P o P part of t he trial.
C o nsi deri n g a dr o p -o ut rate of 1 0 % f or s u bjects n ot e val ua ble f or D L T assess me nt i n P hase Ia, 
a p pr o xi matel y 1 6 5 s u bjects nee d t o be incl u de d i n t he trial.
Pri m ar y e n d p oi nts: 

P hase Ia ( Ar m A): 
o
Occ urre nce of D L T u p t o 5 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
palliati ve fracti o nate d R T .

P hase Ia ( Ar m B): 
o
Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
sta n dar d C R T ( wit h cis plati n) wit h c urati ve i nte nt.

P hase I b ( Ar m A) – first 3 s u bjects: 
o
Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4
i n c o m bi nati o n wit h 
c urati vel y i nte n de d fracti o nate d R T.

P hase I b: Safet y a n d t olera bilit y as f oll o ws:
o
Occ urre nce of treat me nt- e mer ge nt a d verse e ve nts (T E A Es ) (se verity gra d e d acc or di n g 
t o Nati o nal Ca ncer I nstit ute [N CI ] C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts 
[C T C A E ] v 4. 0 3).
o
Res ults of la b orat or y tests, vital si g ns, electr ocar di o gra ms ( E C Gs).
Sec o n d ar y e n d p oi nts: 

P hase Ia ( Ar m A a n d Ar m B): Safet y e n d p oi nts : 
o
Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 4 9
o
Res ults of la b orat or y tests, vital si g ns, E C Gs.

Efficac y  para meters
o
Best o verall res p o nse base d o n t u m or e val uati o ns ma de b y In vesti gat or i n acc or da nce 
wit h R E CI S T ( Res p o nse e val uati o n criteria i n s oli d t u m ors) v 1. 1
o
T u m or size meas ure me nt 
base d o n I n vesti gat or assess me nt i n acc or da nce wit h 
R E CI S T v 1. 1
o
P F S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o pr o gressi ve disease 
( per R E CIS T v 1. 1) base d o n t he I n vesti gat or assess me nt or deat h fr o m a n y ca use, a n d 
l ocal/l ocal re gi o nal t u m or c o ntr ol ( P hase I b, Ar m B e x pa nsi o n c o h ort)
o
O S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o t he date of deat h fr o m 
a n y ca use.
P h ar m ac o ki netic en d p oi nt s - c a ps ule: Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part: 
a.
Fracti o n D a y  1 – ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ), ti me t o reac h 
ma xi m u m o bser ve d c o nce ntrati o n (tma x ), area u n der t he c o nce ntrati o n-ti me c ur ve 
( A U C) fr o m ti me zer o t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n (A U C 0-t),
A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y (A U C 0- ∞), a p pare nt ter mi nal half-life
(t1/ 2), oral cleara nce (C L /f), ap pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase
(Vz/f )
b.
Fracti o n D a y  1 0 - Cma x , tma x , A U C o ver t he d osi n g i nter val after m ulti ple d osi n g
(A U C τ), A U C 0 - ∞, t1/ 2, oral cleara nce at stea d y state ( C L ss/f), a p pare nt v ol u me of 
distri b uti o n at stea d y  state ( Vss/f), acc u m ulati o n rati o f or A U C c ur ve
( Racc[ A U C]), acc u m ulati o n rati o f or ma xi m u m c o nce ntrati o n ( Racc[ Cma x ]).
P h ar m ac o ki netic e n d p oi nts - t a blet: Plas ma P K para meters of M 3 8 1 4 f or P hase Ia part: 
a.
Fracti o n Da y  1 – Cma x , tma x , A U C0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f
b.
Fracti o n Da y  6 - Cma x , tma x , A U C 0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f
c.
Fracti o n Da y  1 0 - Cma x , tma x , A U Cτ, A U C0 - ∞, t1/ 2, C Lss/f, Vss/f, Racc[ A U C], 
R acc[ Cma x ].
P o p ulati o n P K para meters f or P hase I b a n d t he a ncillar y c P o P part of t he trial will be re p orte d 
i n a se parate P K re p ort, w hic h will n ot be part of t he Cli nical Trial Re p ort f or t his trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 4 9
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a: 
I ncl usi o n criteria

P h ase I a p art : a d va nce d s oli d t u m ors or metastases i ncl u di n g l ym p h o ma l ocalize d i n t he 
hea d a n d nec k re gi o n or t h ora x wit h a n i n dicati o n f or fracti o nate d palliati ve R T ( Ar m A); 
or treat me nt-naï ve S C C H N eli gi ble f or fracti o nate d c urati vel y i nte n de d R T wit h c o nc urre nt 
cis plati n ( Ar m B)

P h ase I b part : treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n or
c o nc urre nt c he m ora diati o n ( Ar m A e x pa nsi o n c o h ort) or treat me nt-naï ve S C C H N eli gi ble 
f or fracti o nate d c urati vel y i nte n de d R T wit h c o nc urre nt cis plati n ( Ar m B e x pa nsi o n c o h ort)

A ncill ar y c P o P p art : a n y tu m or wit h at least 2 (s u b)c uta ne o us t u m or/ metastases at least 
2 c m a part w hic h are R T naï ve wit h a n i n dicati o n f or hi g h d ose palliati ve R T 

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des ( P hase Ia a n d I b). If n o 
arc hi val material is a vaila ble t he n a fres h bi o ps y s h o ul d be ta ke n

Willi n g t o ha ve
t u m or bi o psies c ollecte d i n t he a ncillar y c P o P part of t he trial

Meas ura ble or e val ua ble disease b y  RE CI S T v 1. 1 ( n ot re q uire d f or t he a ncillar y c P o P part 
of t he trial )

E aster n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us ( E C O G P S) ≤1

Life e x pecta nc y of ≥3 m o nt hs
( P hase Ia, Ar m A) or ≥6 m o nt hs (P hase Ia, Ar m B a n d 
P hase I b)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 / 1 4 9

Fe male s u bjects of c hil d beari n g p ote ntial a n d male s u bjects wit h fe male part ners of 
c hil d beari n g p ote ntial m ust be willi n g t o a v oi d pre g na nc y .
Mai n e xcl usi o n criteria f or P hase Ia a n d P hase I b:

C he m ot hera p y, i m m u n ot hera py, h or m o nal t hera p y, bi ol o gic t hera p y, or a n y ot her 
a ntica ncer t hera p y or I M P wit hi n 2 8 da y s of first trial dr u g i nta ke f or P hase Ia s u bjects, a n d 
a n y pri or t hera p y f or P hase I b s u bjects. F or s u bjects wit h ra pi dly gr o wi n g t u m ors l ocalize d 
i n t he hea d a n d nec k re gi o n or t h ora x w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 da ys, 
i ncl usi o n ma y ta ke place if t here is n o resi d ual t o xicit y fr o m pre vi o us treat me nt ( ma xi m u m
C T C A E G ra de 1)

Pri or R T t o t he sa me re gi o n wit hi n 1 2 m o nt hs
(P hase Ia, Ar m A ; s u bjects wit h t u m ors 
l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x) or at a n y t i me pre vi o usl y ( P hase Ia, Ar m B ; 
treat me nt-naï ve s u bjects wit h S C C H N a n d P hase I b; treat me nt-naï ve s u bjects wit h Sta ge III 
A/ B N S C L C or S C C H N )

E xte nsi ve pri or R T o n ≥3 0 % of b o ne marr o w reser ve as j u d ge d b y t he I n vesti gat or or pri or 
b o ne marr o w/ste m cell tra ns pla ntati o n wit hi n 5 y ears bef ore trial start.

P o or vital or ga n f u ncti o ns defi ne d as: 
o
B o ne marr o w i m pair me nt as e vi de nce d b y  he m o gl o bi n < 1 0. 0 g/ d L , ne utr o p hil 
c o u nt < 1. 0 × 1 0 9/ L, platelets < 1 0 0 × 1 09/ L
o
Re nal i m pair me nt as e vi de nce d b y  ser u m creati ni ne > 1. 5 × u p per li mit of 
n or mal ( U L N) 
o
Li ver f u ncti o n a b n or malit y as defi ne d b y  total bilir u bi n > 1. 5 × U L N or as partate 
a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase ( A L T) > 2. 5 × U L N (e xce pt 
f or s u bjects wit h li ver i n v ol ve me nt, w h o ca n ha ve A S T/ A LT > 5 × U L N)

Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat ma y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he I MP, c urre nt use of 
perc uta ne o us e n d osc o pic gastr ost o m y ( P E G) t u bes

Si g nifica nt car diac c o n d ucti o n a b n or malities, i ncl u di n g a hist or y  of l o n g Q Tc s yn dr o me 
a n d/ or pace ma ker, or i m paire d car di o vasc ular f u ncti o n s uc h as Ne w Y or k Heart Ass ociati o n 
classificati o n sc ore > 2 .

S u bjects c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial 
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of c yt oc hr o me P 4 5 0 
( C Y P) 3 A or C Y P 2 C 1 9 ( m ust st o p at least 1 wee k pri or), p ote nt i nd ucers of C Y P 3 A or 
C Y P 2 C 1 9 ( m ust st o p at least 3 wee ks pri or), or dr u gs mai nl y meta b olize d b y  C Y P 3 A wit h 
a narr o w t hera pe utic i n de x ( m ust st o p at least o ne da y  pri or).

S u bjects c urre ntl y r ecei vi n g H 2-bl oc ker or pr ot o n p u m p i n hi bit ors ( or u na ble t o st o p at least 
5 da y s pri or t o t he first treat me nt).

If t he pla n ne d ra diati o n fiel d i ncl u des a n y part of t he es o p ha g us a n d t he s u bject has 
s ym pt o ms 
of o n g oi n g es o p ha gitis, t he s u bject is n ot eli gi ble, u nless a n es o p ha geal 
e n d osc o p y r ules o ut t he prese nce of es o p ha gitis.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 4 9
 ( 
 t a blet f or m ul ati o n of M 3 8 1 4: 
M 3 8 1 4
will be pr o vi de d as 
 ta blet f or m ulati o n of 5 0 m g, f or oral a d mi nistrati o n. D osi n g 
sc he d ule of t he ta blet f or m ulati o n f oll o ws t he descri pti o n gi ve n f or t he ca ps ule f or m ulati o n 
a b o ve. T he ta blet f or m ulati o n will be i nitiall y assesse d i n P hase Ia Ar m A ta ki n g i nt o acc o u nt 
t he a vaila ble safety, t olera bilit y a n d P K res ults fr o m t he ca ps ule. Sta n dar d 3 + 3 d ose escalati o n 
desi g n criteria will a p pl y. E val uati o n o f si n gle d ose P K data after a d mi nistrati o n of t he ta blet 
a n d t he ca ps ule i n t he sa me s u bject will su p p ort t he selecti o n of ta blet d oses i n P hase Ia Ar m B ,
t he P hase Ib parts a n d i n t he a d diti o nal c o h orts of M 3 8 1 4 i n t he a ncillar y c P o P part of t he trial .
C o nc urre nt cis pl ati n - Dose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule:
C o nc urre nt cis plati n will be a d mi nistere d i n c o m bi nati o n wit h t he I MP i n s u bjects wit h 
S C C H N i ncl u de d i n P hase Ia Ar m B a n d t he S C C H N e x pa nsi o n c o h ort i n P hase I b. T he d ose 
a n d d ose re gi me n of cis plati n is t o be a p plie d i n li ne wit h c urre nt me dical g ui deli nes ( N C C N, 
A C C P/ A S C O , a n d E S M O) wit h refere nce t o t he Sta n dar d of Care (S o C ) f or c o nc urre nt C R T 
wit h cis plati n i n t he treat me nt of s u bjects wit h S C C H N . Cis plati n will be gi ve n t wice at a d ose 
of 1 0 0 m g/ m 2 or wee kl y at a d ose of 4 0 m g/ m 2.
Pl a n ne d tri al a n d tre at me nt d ur ati o n per s u bje ct: 
Treat me nt d urati o n is e x pecte d t o be a p pr o xi matel y  2 wee ks ( Ar m A) or 7 wee ks ( Ar m B) f or 
t he P hase Ia part, 6- 7 wee ks f or t he P hase I b part, a n d 2 da y s f or t he a ncillar y c P o P part.
St atistic al met h o ds:
I n the P hase Ia part , f or eac h ar m ( A a n d B) t he sa m ple size will de pe n d o n t he n u m ber of D L T s 
o bser ve d at t he differe nt d ose le vels a n d t he n u m ber of teste d or e x pa n de d d ose le vels f or M 3 8 1 4 . 
S u bject s will be e nr olle d i n c o h orts of 3 s u bjects. 
T he P hase I b part c o nsists of o ne e x pa nsi o n c o h ort per ar m fr o m t he P hase Ia part. F or Ar m A, 
t he e x pa nsi o n c o h ort will e x pl ore t he acti vit y of M 3 8 1 4
c o m bi ne d wit h R T i n treat me nt-naï ve
s u bjects wit h S ta ge III A/ B N S C L C . T he c o h ort will e nr oll u p t o 2 7 e val ua ble s u bjects i ncl u di n g 
t he safety r u n-i n part, bri n gi n g t he a ntici pate d ma xi m u m sa m ple size f or t he P hase Ia/I b parts t o 
7 5 s u bjects f or Ar m A . A sa m ple size of 2 7 e val ua ble s u bjects will e na ble t he l o wer li mit of a 
2- si de d 9 5 % c o nfi de nce i nter val ( CI ) f or t he res p o nse rate t o e xte n d n o f urt her t ha n a n a bs ol ute 
2 0 % fr o m t he e x pecte d pr o p orti o n of 5 0 %, t here b y ens uri n g t he l o wer li mit is n o less t ha n t he 
hist orical c o ntr ol of 3 0 % i n treat me nt-naï ve s u bjects wit h Sta ge III A/ B N S C L C. 
F or Ar m B, t he a ntici pate d sa m ple size i n t he escalati o n part is 3 0 partici pa nts (t o get her f or 
ta blet a n d ca ps ule). T he e x pa nsi o n c o h ort will e x pl ore t he safety, t olera bilit y an d efficac y of 
M 3 8 1 4
c o m bi ne d wit h C R T ( wit h cis plati n) i n treat me nt-naï ve s u bjects wit h S C C H N. A 
sa m ple size of u p t o 2 7 e val ua ble s u bjects will be e nr olle d t o c o nfir m safet y a n d t olera bilit y of 
t he c o m bi nati o n . T o get her, t his bri n gs t he a ntici pate d sa m ple size f or t he P hase Ia/I b parts t o 
5 7 s u bjects f or Ar m B .
F or t he a ncillar y c P o P part of t he trial c o n d ucte d i n p arallel wit h t he P hase Ia part, a fi xe d n u m ber 
of 3 s u bjects will be e nr olle d at t he t w o l o wer fi xe d d ose le vels a n d 5 s u bjects will be e nr olle d at 
t he R P 2 D . Ass u mi n g a c orrelati o n bet wee n t he f ol d i n d ucti o n of t he mar ker a n d t he d ose is 0. 6 9, 
t he p o wer of detecti n g a li near relati o ns hi p is 8 0 % wit h a n al p ha-le vel of 5 % ( 2-si de d). I n case 
t he P D res ults d o n’t all o w detect i o n of s ufficie nt m o d ulati o n of tar get e n ga ge me nt i.e., a clear 
d ose/effect relati o ns hi p bet wee n le vels i n pre- a n d o n treat me nt t u m or bi o psies, a d diti o nal d ose 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 4 9
le vel(s) c o ul d be e x pl ore d u p o n S M C decisi o n acc or di n g t o t he fi n di n gs d uri n g t he escalati o n 
p hase i n P hase Ia. A p pr o xi matel y  12 a d diti o nal s u bjects ma y  be e nr olle d i n t he a ncillar y cP o P 
part of t he trial usi n g M 3 8 1 4 
 f or m ulati o n, t h us lea di n g t o a ma xi m u m sa m ple size i n t he 
a ncillar y c P o P part of 2 3.
T he a ntici pate d t otal n u m ber of e val ua ble s u bjects t o be i ncl u de d i n t he t hree parts of t he trial
wit h a d diti o nal c o h orts i n t he a ncillar y c P o P part of t he trial is t heref ore 1 5 5 . C o nsi deri n g a dr o p -
o ut rate of 1 0 % f or s u bjects n ot e val ua ble f or D L T assess me nt i n P hase Ia, a p pr o xi matel y 
1 6 5 s u bjects nee d t o be e nr olle d i n t he trial.
F or t he P hase Ia part , t he n u m ber a n d pr o p orti o n of s u bjects e x perie nci n g a D L T will be re p orte d 
b y f or m ulati o n a n d d ose le vel, base d o n t he o bser vati o n of D L Ts u p t o 5 wee ks ( Ar m A) or 
1 2 wee ks ( Ar m B) after t he first d ose of M 3 8 1 4
ta ki n g i nt o acc o u nt t he k n o w n t o xicities wit h
R T al o ne.
F or t he safet y r u n-i n part of P hase I b (first 3 s u bjects i n Ar m A) , t he n u m ber of s u bjects 
e x perie nci n g a D L T u p t o 1 2 wee ks after t he first d ose of M 3 8 1 4 will als o be re p orte d. S u bjects 
i ncl u de d i n t he r u n-i n part will be a nalyz e d se paratel y fro m t he re mai ni n g s u bjects of P hase I b.
All sec o n dar y  en d p oi nts will be s u m marize d b y mea n of descri pti ve statistics i ncl u di n g 9 5 % CI  
b y  d ose le vel a n d o verall, u nless ot her wise state d. Res p o nse rate will be calc ulate d, a n d P F S a n d 
O S will be e val uate d f or t he e x pa nsi o n c o h ort o nly.
A d verse e ve nts will be c o de d acc or di n g t o t he latest a vaila ble versi o n of t he Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A). Se verit y of A Es will be gra de d usi n g t he C T C A E (v 4. 0 3) 
t o xicit y gra des. A d verse e ve nts relate d t o t he trial me dicati o n will be defi ne d as a n y A E 
c o nsi dere d relate d t o M 3 8 1 4 . I n a d diti o n, missi n g classificati o ns c o ncer ni n g trial me dicati o n 
relati o ns hi ps will be c o nsi dere d relate d t o t he trial dr u g. S u bject s w h o ter mi nate treat me nt will 
be dis pla y e d in a b y -s u bject listi n g, a n d s u m marize d b y  pri mar y wit h dra wal reas o n f or eac h 
treat me nt gr o u p. All re p orte d deat hs d uri n g t hera p y  an d deat hs wit hi n 3 0 da y s after last d ose of 
trial treat me nt will be ta b ulate d a n d t he pri mar y ca use of deat h will be re p orte d (f or all s u bjects 
e nr olle d). La b orat or y  res ults will be classifie d b y  gra de acc or di n g t o t he C T C A E v 4. 0 3 . T he 
w orst o n -trial gra des after t he first d ose of trial treat me nt will be s u m marize d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 4 9
T a ble 1
Sc he d ule of Assess me nts – P h ase I a ( Ar m A): C a ps ule C o h orts
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  
F U
L o n g -t er m 
S af et y  F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , a n d 
3 1 2 x
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
- 
-
± 2
± 2
± 7 
± 7
± 7
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 o nl y
I nf e cti o n s cr e e n ( h e p atiti s B a n d 
C) , o pti o n al HI V t e ste
X
Vit al si g n s f
X g
X
X 
X 
X
X
X
X
X h
P h y si c al e x a mi n ati o n
X 
X
X 
X 
X
X
X
X
X i
Cli ni c al e x a mi n ati o n of bl e e di n g
X 
X
X 
X 
X
X
E s o p h a g e al e n d o s c o p y (if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X 
X 
X
X
X
X
X
E C O G P S
X
X 
X
P T D 3 0 o nl y
X
X
X i
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  
F U
L o n g -t er m 
S af et y  F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , a n d 
3 1 2 x
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
- 
-
± 2
± 2
± 7 
± 7
± 7
A d v er s e e v e nt a s s e s s m e nt
X 
X
X 
X 
X
X
X j
X j
X j
C o n c o mit a nt m e di c ati o n
X 
X
X 
X 
X
X
H e m at ol o g y k
X 
X
X 
X 
X
X
S er u m c h e mi str y a n d c o a g ul ati o n l
X 
X
X 
X 
X
X
Uri n al y si s ( di p sti c k) m
X
X 
X
P T D 3 0 o nl y
1 2 -l e a d E C G (i n cl u di n g Q T c F)n
X 
X o
X p
T u m or a s s e s s m e nt ( R E CI S T) q
X
X r
X h , r
X h
P K bl o o d s a m pl e s s
X 
X t
X 
X
Ar c hi v al t u m or m at eri al
u
X
S ur vi v al 
X y
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 4 9
A E = a d v er s e e v e nt ; C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s ; e C R F = el e ctr o ni c c a s e r e p ort f or m; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n ; F D = fr a cti o n d a y; 
F U = f oll o w -u p; F/ W =  fr a ctio n p er w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e 
i m a gi n g; P D = p h ar m a c o d y n a mi c s; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a - c orr e ct e d Q T i nt er v al; 
R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s ; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D) ( d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n). P o st -tr e at m e nt D a y ( P T D) ( d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er).
a.
All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or 
a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e . g., if a n e w tr e at m e nt i s st art e d, wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d 
i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s m u st b e d o n e a s pl a n n e d f or P T D 3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, 
s u bj e ct s will b e f ol l o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
c.
F D 1 0 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al fr o m t h e tri al d uri n g t h e tr e at m e nt p eri o d , t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit 
o n F D 1 0 s h o ul d b e p erf or m e d. I n s u c h c a s e s t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit. If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y 
l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
A ll A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 2 1 t o e v al u at e t h e o c c urr e n c e of D L T s.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul ator y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
O nl y r e q uir e d if s u bj e ct h a s n ot st art e d a n e w a ntit u m or tr e at m e nt. If a n e w tr e at m e nt i s st art e d, t h e d at e ( a n d r e gi m e n) m u st b e r e p ort e d i n t h e e C R F.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e  T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 8 d a y s ol d 
w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1- 1 8 0 [ 4 a s s e s s m e nt s]) a n d d uri n g s ur vi v al F U ( e v er y 1 3 w e e k s 
d uri n g D a y 1 8 1 -3 6 5 [ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or 
d et ail s.
t.
Pr e d o s e o nl y .
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e) . If n o ar c hi v al t u m or m at eri al i s a v ail a bl e a 
fr e s h bi op s y m u st b e t a k e n.
D oc u me nt N o. 0 9 0 0 ba be 8 1 1 5 6 2 1 4 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 1 8e 7 2 2
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 5 4 8 0 9 8 _ 4 6 2 6 0 5 9
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 4 9
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 4 9
T a ble 2
Sc he d ule of Assess me nts – P h ase I a ( Ar m A): T a blet C o h orts
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B a n d C), 
o pti o n al HI V t e st e
X
Vit al si g n s f
X g
X
X
X 
X
X 
X 
X
X h
P h y si c al e x a mi n ati o n
X 
X
X
X 
X
X 
X 
X
X i
Cli ni c al e x a mi n ati o n of bl e e di n g
X 
X
X
X 
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
E s o p h a g e al e n d o s c o p y (if r el e v a nt) 
X
E v al u ati o n of all ti s s u e s i n R T ar e a
X
X 
X
X 
X 
X
X
E C O G P S
X
X 
X
P T D 3 0 
o nl y
X 
X
X i
A d v er s e e v e nt a s s e s s m e nt
X 
X
X
X 
X
X 
X j
X j
X j
C o n c o mit a nt m e di c ati o n
X 
X
X
X 
X
X
H e m at ol o g y k
X 
X
X
X 
X
X
S er u m c h e mi str y a n d c o a g ul ati o n l
X 
X
X
X 
X
X
Uri n al y si s ( di p sti c k) m
X
X 
X
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g Q T c F)n
X 
X o
X p
T u m or a s s e s s m e nt ( R E CI S T)q
X
X r
X h , r
X h
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
S h ort -
t er m 
S af et y  
F U
Mi d -
t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U
S ur vi v al 
F U/ E O T a
Tr e at m e nt P eri o d 
(M 3 8 1 4 + R T)
D L T 
P eri o d
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 1 0
P T D 
1 t o 2 1
P T D 
2 2 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
P T D 
1 8 1 t o 3 6 5
M 3 8 1 4
T a bl et y
-
X
X
-
M 3 8 1 4 C a p s ul e
X
R T 3 G y  x 1 0 ( 5 F/ W)b
-
X
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6 z
F D 7
F D 1 0 c /
E T T
P T D 
8, 1 5
P T D 
2 2 d , 3 0
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 a a ,
a n d 
3 1 2 a a
P T D 
2 7 0, 3 6 5
Vi sit Wi n d o w ( d a y s)
- 
-
-
-
± 2 
± 2 
± 7 
± 7
± 7
P K bl o o d s a m pl e s s
X 
X t
X 
X t
X
Ar c hi v al t u m or m at eri alu
X
S ur vi v al 
X x
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; C R T = c h e m or a di ot h er a p y ;
; D L T = d o s e li miti n g t o xi cit y; E C G = 
el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; e C R F = el e ctr o ni c c a s e r e p ort f or m; E O T = E n d of Tri al; E T T = E arl y 
Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n 
i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt 
D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 4 9
N ot e:
Fr a cti o n D a y ( F D) ( d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n). P o st-tr e at m e nt D a y ( P T D) ( d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er). 
a.
All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or 
a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d , wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d 
i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s m u st b e d o n e a s pl a n n e d f or P T D 3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, 
s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
F D 1 0 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al fr o m t h e tri al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit 
o n F D 1 0 s h o ul d b e p erf or m e d. I n s u c h c a s e s t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit. If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y 
l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 2 1 t o e v al u at e t h e o c c urr e n c e of D L T s.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
O nl y r e q uir e d if s u bj e ct h a s n ot st art e d a n e w a ntit u m or tr e at m e nt. If a n e w tr e at m e nt i s st art e d, t h e d at e ( a n d r e gi m e n) m u s t b e r e p ort e d i n t h e e C R F.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e  T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 8 d a y s ol d 
w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s]) a n d d uri n g s ur vi v al F U ( e v er y 1 3 w e e k s 
d uri n g D a y 1 8 1 - 3 6 5 [ 2 a ss e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d by t h e S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or 
d et ail s.
t.
Pr e d o s e o nl y.
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e) . If n o ar c hi v al t u m or m at eri al i s a v ail a bl e a 
fr e s h bi o p s y m u st b e t a k e n.
x.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3
m o nt h s.
y.
S u bj e ct s tr e at e d i n t h e t a bl et t e sti n g c o h ort s of P h a s e I a Ar m A will r e c ei v e t h e t a bl et o n F D 1 -5 a n d F D 7 - 1 0 a n d a r e s p e cti v e si n gl e d o s e str e n gt h of t h e 
c a p s ul e f or m ul ati o n o n F D 6.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 4 9
z.
If F D 6 i s N O T o n a M o n d a y
t h e n it m u st b e s c h e d ul e d t o t a k e pl a c e o n t h e M o n d a y cl o s e st t o F D 6 a s w a s h- o ut o v er t h e w e e k e n d i s r e q uir e d. 
a a.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 4 9
T a ble 3
Sc he d ule of Assess me nts – First 3 S u bjects i n P h ase I b ( Ar m A; N S C L C C o h ort)
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y 
t e st 
(if a p pli c a bl e)
X
P T D 2 2
o nl y
I nf e cti o n s cr e e n ( h e p atiti s 
B a n d C), o pti o n al HI V 
t e stf
X
Vit al si g n s g
X h
X
X 
X
X
X 
X
X
P h y si c al e x a mi n ati o n
X
X
X 
X
X
X 
X
X i
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X 
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n 
R T ar e a
X 
X
X
X 
X
X
E C O G P S
X
X
F D 3 3 o nl y
X 
X
X
A d v er s e e v e nt 
a s s e s s m e nt
X
X
X 
X
X
X 
X j
X j
C o n c o mit a nt m e di c ati o n
X
X
X 
X
X
X
H e m at ol o g y k
X
X
X 
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n l
X
X
X 
X
X
X
Uri n al y si s ( di p sti c k)m
X
X
F D 1 6 a n d 
3 3 o nl y
X
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) n
X
X o
X p
T u m or a s s e s s m e nt 
( R E CI S T)q, r
X
X
X
P K bl o o d s a m pl e s s
X 
X t
X 
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  
F U
L o n g -
t er m 
S af et y  
F U/ E O T a
S ur vi v al F U
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
D L T 
P eri o d / S
h ort -
t er m 
S af et y  
F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D
1 t o 3 7
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D
8, 1 5 , 2 2, 
3 7 e
P T D
8 4
P T D 
4 2, 1 2 6, 
1 6 8, 1 8 0 , 
2 1 0 x , 2 7 0,
3 1 2 x , a n d
3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
- 
- 
- 
-
-
± 2 
± 7 
± 7
-
Ar c hi v al t u m or m at eri al u
X
S ur vi v al 
X y
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W
= fr a cti o n p er 
w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n 
S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n. P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er.
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e . g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 4 9
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If FD 1 0 i s o n a Fri d a y, P K, P D, s af et y l a b or at or y , a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n F D 3 3
s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 3 7 t o e v al u at e t h e o c c urr e n c e of D L T s.
f.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
g.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht . S e e S e cti o n 7. 4. 4 f or d et ail s.
h.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
i.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
j.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
k.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
l.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
m.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
n. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
p. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
q.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
r.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1- 1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
s.
P K s a m pl e s f or t h e fir st 3 s u bj e ct s i n P h a s e I b will f oll o w t h e s a m pli n g f or P h a s e I a a s d et ail e d i n T a bl e 9.  S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e 
S M C b a s e d o n e m er gi n g d at a. S e e S e cti o n 7. 5. 1 f or d et ail s.
t.
Pr e d o s e o nl y .
u.
M a n d at or y ar c hi v al t u m or m at eri a l s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 / 1 4 9
T a ble 4
Sc he d ule of Assess me nts – P h ase I b (Ar m A; N S C L C C o h ort)
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0v , 
2 7 0, 3 1 2 v , 
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B 
a n d C), o pti o n al HI V t e st e
X
Vit al si g n s f
X g
X
X
X
X
X
P h y si c al e x a mi n ati o n
X
X
X
X
X
X
X h
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X
X
X
E s o p h a g e al e n d o s c o p y (if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X
X
X
X
X
E C O G P S
X
-
F D 3 3 o nl y
P T D 3 0
o nl y
X
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X
X i
X i
C o n c o mit a nt m e di c ati o n
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4 + R T)
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 33 ( 5 F/ W)b
X
X
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 
2 6 a n d 
3 3 / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0v , 
2 7 0, 3 1 2 v , 
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
H e m at ol o g y j
X
X
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n k
X
X
X
X
X
Uri n al y si s ( di p sti c k) l
X
F D 1 6 a n d 3 3
o nl y
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) m
X
X n
X o
T u m or a s s e s s m e nt 
( R E CI S T)p, q
X
X
X
P K bl o o d s a m pl e s r
X
X
Ar c hi v al t u m or m at eri al s
X
S ur vi v al 
X w
C T = c o m p ut e d t o m o gr a p h y; 
; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y 
Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U
= f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; 
H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
;  
 
; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a - c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n. P o st -tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar 
l at er
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 4 9
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s
aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D 3 6 5 . Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, a n d s af et y l a b or at or y s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d , t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n F D 3 3
s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
g.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
h.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
i.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s .
j.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
k.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
l.
U ri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
m.
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
n. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e.
o. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
p.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1.
B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
q.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g-t er m s af et y F U (e v er y 6 w e e k s d uri n g D a y 3 1 - 1 8 0 [4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]) . T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
r.
S p ar s e P K s a m pl e s will b e c oll e ct e d a s d et ail e d i n T a bl e 9.  T h e s e s a m pli n g ti m e p oi nt s mi g ht b e r e-s c h e d ul e d b a s e d o n P K r e s ult s fr o m P h a s e I a b y t h e 
S M C.
s.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
If n o ar chi v al m at eri al i s a v ail a bl e t h e n a fr e s h 
bi o p s y s h o ul d b e t a k e n .
v.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s wil l b e p erf or m e d at t h e s e vi sit s.
w.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 4 9
T a ble 5
Sc he d ule of Assess me nts – P h ase I a ( Ar m B; S C C H N C o h ort)
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n 
crit eri a
X 
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y 
t e st 
(if a p pli c a bl e)
X
P T D 2 8 o nl y
I nf e cti o n s cr e e n ( h e p atiti s 
B a n d C), o pti o n al HI V 
t e stf
X
H P V st at u s i n t u m or g
X
A u di o gr a m h
X
Vit al si g n s i
X j
X
X 
X
X
X
X
X
P h y si c al e x a mi n ati o n
X 
X
X 
X
X
X
X
X k
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X 
X
X 
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n 
R T ar e a
X 
X
X
X
X
X
E C O G P S
X
X
L a st F D o nl y
X
X
X
A d v er s e e v e nt 
a s s e s s m e nt
X 
X
X 
X
X
X
X l
X l
C o n c o mit a nt m e di c ati o n
X 
X
X 
X
X
X
H e m at ol o g y m
X 
X
X 
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n n
X 
X
X 
X
X
X
Uri n al y si s ( di p sti c k) o
X
X
F D 1 6 a n d 
l a st F D o nl y
X
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) p
X 
X q
X r
X r
X r
X r
T u m or a s s e s s m e nt 
( R E CI S T)s , t
X
X
X
P K bl o o d s a m pl e s u
X 
X v
X 
X
Ar c hi v al t u m or m at eri al w
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
D L T E v al u ati o n P eri o d
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al 
F U
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + C i s pl ati n)
D L T P eri o d /
S h ort -t er m 
S af et y  F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D
1 t o 3 5
P T D
1 t o 9 0
P T D
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1 
F D 2 
F D 6
F D 1 0 c
F D 1 6 , 21 , 
2 6, 3 1 a n d 
l a st F D/ E T Td
P T D
7 , 14 , 21 , 28, 
3 5 e
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0z, 
2 7 0, 3 1 2 z, a n d 
3 6 5
-
Vi sit Wi n d o w ( d a y s)
- 
- 
- 
- 
-
-
± 2
± 7
± 7
-
S ur vi v al 
X a a
A E = a d v er s e e v e nt; C T = c o m p ut e d t o m o gr a p h y; 
 D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U = f oll o w -u p; F/ W
= fr a cti o n p er 
w e e k; G y = G r a y; H C G = h u m a n c h ori o ni c g o n a d otr o pi n; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; H P V = h u m a n p a pill o m a vir u s; M RI = m a g n eti c r e s o n a n c e i m a gi n g; 
; 
; P K = p h ar m a c o ki n eti c s; P T D = P o st- tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = 
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n ( pl u s ci s pl ati n o n F D s a s s p e cifi e d a b o v e). P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s 
of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar l at er .
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, s af et y l a b or at or y, a n d uri n al y si s s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 - 3 5 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n t h e 
l a st F D s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T er mi n ati o n vi sit.
e.
All A E s will b e c oll e ct e d fr o m F D 1 u p t o P T D 3 3 -3 5 t o e v al u at e t h e o c c urr e n c e of D L T s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 4 9
f.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
g.
I m m u n o hi st o c h e mi str y i n t u m or m at eri al.
h.
A s n e e d e d a c c or di n g t o l o c al g ui d eli n e s.
i.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 f or d et ail s.
j.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
k.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
l.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
m.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
n.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
o.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
p. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
q. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e .
r.
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
s.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
t.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
u.
P K s a m pl e s will f oll o w t h e s a m pli n g f or P h a s e I a a s d et ail e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d b y t h e S M C b a s e d o n e m er gi n g d at a. S e e 
S e cti o n 7. 5. 1 f or d et ail s.
v.
Pr e d o s e o nl y.
w.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e).
z.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
a a.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 4 9
T a ble 6
Sc he d ule of Assess me nts – P h ase I b (Ar m B; S C C H N C o h ort)
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + Ci s pl ati n )
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 26, 
3 1 a n d l a st 
F D / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0x , 
2 7 0, 3 1 2 x ,
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m β -H C G pr e g n a n c y t e st 
(if a p pli c a bl e)
X
P T D 3 0 
o nl y
I nf e cti o n s cr e e n ( h e p atiti s B 
a n d C), o pti o n al HI V t e st e
X
H P V st at u s i n t u m or f
X
A u di o gr a m g
X
Vit al si g n s h
X i
X
X
X
X
X
P h y si c al e x a mi n ati o n
X
X
X
X
X
X
X j
Cli ni c al e x a mi n ati o n of 
bl e e di n g
X
X
X
X
X
E s o p h a g e al e n d o s c o p y ( if 
r el e v a nt)
X
E v al u ati o n of all ti s s u e s i n R T 
ar e a
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt P eri o d
(M 3 8 1 4
+ R T + Ci s pl ati n )
S h ort -t er m 
S af et y  F U
Mi d -t er m 
S af et y  F U
L o n g -t er m 
S af et y  F U/
E O T a
S ur vi v al F U
Tri al D a y s
D a y -2 1 t o 
D a y - 1
F D 1 t o F D 3 3 - 3 5
P T D 
1 t o 3 0
P T D
1 t o 9 0
P T D 
3 1 t o 3 6 5
-
M 3 8 1 4
R T 2 G y  x 3 3 - 3 5 ( 5 F/ W)b
Ci s pl ati n
-
X
X
1 0 0 m g/ m 2 t wi c e (F D 1, 3 1 ) or 4 0 m g/ m2 w e e kl y
-
-
-
-
Vi sit D a y s
-2 1 t o - 1
F D 1
F D 1 0 c
F D 6, 1 6 , 21 , 26, 
3 1 a n d l a st 
F D / E T Td
P T D 
8, 1 5, 2 2 ,
3 0
P T D
8 4
P T D 
4 2, 1 2 6, 1 6 8, 
1 8 0 , 2 1 0x , 
2 7 0, 3 1 2 x ,
a n d 3 6 5
-
Vi sit Wi n d o w ( d a y s)
-
-
-
-
± 2
± 7
± 7
-
E C O G P S
X
-
L a st F D o nl y
P T D 3 0 
o nl y
X
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X
X k
X k
C o n c o mit a nt m e di c ati o n
X
X
X
X
X
H e m at ol o g y l
X
X
X
X
X
S er u m c h e mi str y a n d 
c o a g ul ati o n m
X
X
X
X
X
Uri n al y si s ( di p sti c k) n
X
F D 1 6 a n d l a st F D
o nl y
P T D 3 0 
o nl y
1 2 -l e a d E C G (i n cl u di n g 
Q T c F) o
X
X p
X q
X q
X q
X q
T u m or a s s e s s m e nt 
( R E CI S T)r, s
X
X
X
P K bl o o d s a m pl e s t
X
X
Ar c hi v al t u m or m at eri al
u
X
S ur vi v al 
X y
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 4 9
C T = c o m p ut e d t o m o gr a p h y; ct D N A = cir c ul ati n g t u m or D N A; D L T = d o s e li miti n g t o xi cit y; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y 
Gr o u p p erf or m a n c e st at u s; E O T = E n d of Tri al; E T T = E arl y Tr e at m e nt T er mi n ati o n; F D = fr a cti o n d a y; F U
= f oll o w -u p; F/ W = fr a cti o n p er w e e k; G y = G r a y; 
H C G = h u m a n c h ori o ni c g o n a d otr o pi n ; HI V = h u m a n i m m u n o d efi ci e n c y vir u s; H P V = h u m a n p a pill o m a vir u s; M RI
= m a g n eti c r e s o n a n c e i m a gi n g; P D = 
p h ar m a c o d y n a mi c s; P G x = p h ar m a c o g e n eti c s; P K = p h ar m a c o ki n eti c s; P T D = P o st -tr e at m e nt D a y; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; R E CI S T = R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y; S M C = S af et y M o nit ori n g C o m mitt e e.
N ot e:
Fr a cti o n D a y ( F D): d a y s w h e n R T a n d M 3 8 1 4
i s gi v e n ( pl u s ci s pl ati n o n F D s a s s p e cifi e d a b o v e). P o st-tr e at m e nt D a y ( P T D): d a y s i n t h e p eri o d st arti n g a s 
of e n d of t h e tr e at m e nt p eri o d u ntil 1 y e ar l at er .
a.
All s u bj e ct s will b e f oll o w e d u p f or s ur vi v al u ntil 1 2 m o nt h s aft er t h e l a st s u bj e ct h a s st o p p e d R T / C R T. All s u bj e ct s will b e f oll o w e d u p f or r e s p o n s e u ntil 
1 2 m o nt h s aft er R T i s c o m pl et e d, or e arli er d u e t o a n y r e a s o n w h er e b y t u m or a s s e s s m e nt s
ar e n o l o n g er a p pli c a bl e ( e. g., if a n e w tr e at m e nt i s st art e d, 
wit h dr a w al of c o n s e nt). T h e r e a s o n f or e arl y di s c o nti n u ati o n s h o ul d b e c a pt ur e d i n t h e s o ur c e d o c u m e nt. If E O T o c c ur s b ef or e P T D 3 6 5, all a s s e s s m e nt s 
m u st b e d o n e a s pl a n n e d f or P T D
3 6 5. Aft er c o m pl eti n g t h e P T D 3 6 5 vi sit, s u bj e ct s will b e f oll o w e d u p f or s ur vi v al vi a p h o n e c all e v er y 3 m o nt h s, 
w h er e v er p o s si bl e.
b.
R T t o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g.
c.
If F D 1 0 i s o n a Fri d a y, P K, P D, a n d s af et y l a b or at or y s a m pli n g m u st b e d o n e o n F D 9.
d.
F D 3 3 - 3 5 i s t h e d a y of t h e l a st d o s e of R T. I n c a s e of pr e m at ur e wit h dr a w al d uri n g t h e tr e at m e nt p eri o d, t h e i n v e sti g ati o n s s c h e d ul e d f or t h e vi sit o n t h e 
l a st F D s h o ul d b e p erf or m e d. I n s u c h c a s e s, t hi s vi sit will b e c o n si d er e d t h e E arl y Tr e at m e nt T e r mi n ati o n vi sit.
e.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
f.
I m m u n o hi st o c h e mi str y i n t u m or m at eri al.
g.
A s n e e d a c c or di n g t o l o c al g ui d eli n e s.
h.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht. S e e S e cti o n 7. 4. 4 for d et ail s.
i.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
j.
P h y si c al e x a m will r e p ort fi n di n g s i n t h e irr a di at e d ar e a d uri n g all F U p eri o d s.
k.
E v al u ati o n of o n g oi n g tr e at m e nt -e m er g e nt a d v er s e e v e nt s.
l.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
m.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
n.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s.
o. 
1 2 -l e a d r e sti n g E C G i n tri pli c at e.
p. 
1 2 -l e a d E C G t o b e p erf or m e d pr e d o s e a n d o n c e at 2 t o 3 h o ur s p o st d o s e.
q. 
1 2 -l e a d E C G t o b e p erf or m e d at 2 h o ur s p o st d o s e.
r.
T u m or i m a gi n g b y C T or M RI at b a s eli n e t o d o c u m e nt e xt e nt of l e si o n s a n d a b s e n c e of m et a st a s e s ( M 0 st a g e) a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or 
e v al u ati o n c a n b e u p t o 2 8 d a y s ol d w h e n tr e at m e nt st art s.
s.
T u m or a s s e s s m e nt s t o b e d o n e at l o n g -t er m s af et y F U ( e v er y 6 w e e k s d uri n g D a y 3 1-1 8 0 [ 4 a s s e s s m e nt s] a n d e v er y 1 3 w e e k s d uri n g D a y 1 8 1 -3 6 5 
[ 2 a s s e s s m e nt s]). T u m or a s s e s s m e nt will n ot b e r e p e at e d o n P T D 1 8 0.
t.
S p ar s e P K s a m pl e s w ill b e c oll e ct e d a s d et ail e d i n T a bl e 9.  T h e s e s a m pli n g ti m e p oi nt s mi g ht b e r e- s c h e d ul e d b a s e d o n P K r e s ult s fr o m P h a s e I a b y t h e 
S M C.
u.
M a n d at or y ar c hi v al t u m or m at eri al s s a m pl e d b ef or e st art of t h e tr e at m e nt ( m o st r e c e nt m at eri al s a v ail a bl e). If n o ar c hi v al m at eri al i s a v ail a bl e t h e n a fr e s h 
bi o p s y s h o ul d b e t a k e n .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 4 9
w.
Pr e d o s e w h ol e bl o o d a n d pl a s m a s a m pli n g f or P G x.
x.
P T D 2 1 0 a n d 3 1 2 will c o n si st of p h o n e c all s t o e v al u at e l o n g t er m R T t o xi cit y. N o ot h er a s s e s s m e nt s will b e p erf or m e d at t h e s e vi sit s .
y.
C a n b e f oll o w e d u p vi a p h o n e c all e v er y 3 m o nt h s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 4 9
T a ble 7
Sc he d ule of Assess me nts – A ncill ar y Cli nic al Pr o of -of- Pri nci ple P art
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt D ur ati o n
F U
S af et y  F oll o w u p
a n d E n d of Tri al
Tri al D a y s
D a y -2 1 t o - 1
1
2
3 t o 1 0
1 1 t o 32
M 3 8 1 4
-
-
X
-
-
R T: 1 0 -2 5 G y a
L e si o n 1
L e si o n 2
Tri al Vi sit D a y
– 2 1 t o – 1
1 b
2
1 0
3 2
Vi sit wi n d o w ( d a y s)
-
-
-
± 1
± 2
Si g n e d i nf or m e d c o n s e nt
X
I n cl u si o n/ e x cl u si o n crit eri a
X
D e m o gr a p h y
X
M e di c al hi st or y
X
S er u m pr e g n a n c y t e st 
(if a p pli c a bl e)
X
I nf e cti o n s cr e e n ( h e p atiti s B a n d C ), o pti o n al 
HI V t e st c
X
Vit al si g n s d
X e
X f
X f
X
P h y si c al e x a mi n ati o n
X
E v al u ati o n of all ti s s u e s i n R T ar e a
X
X
X
X
E C O G P S
X
A d v er s e e v e nt a s s e s s m e nt
X
X
X
X
X g
C o n c o mit a nt m e di c ati o n
X
X
X
X
H e m at ol o g y h
X
X
X
S er u m c h e mi str y a n d c o a g ul ati o n i
X
X
X
Uri n al y si s ( di p sti c k)j
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 4 9
Tri al P eri o d s
S cr e e ni n g
Tr e at m e nt D ur ati o n
F U
S af et y  F oll o w u p
a n d E n d of Tri al
Tri al D a y s
D a y -2 1 t o - 1
1
2
3 t o 1 0
1 1 t o 32
M 3 8 1 4
-
-
X
-
-
R T: 1 0 -2 5 G y a
L e si o n 1
L e si o n 2
Tri al Vi sit D a y
– 2 1 t o – 1
1 b
2
1 0
3 2
Vi sit wi n d o w ( d a y s)
-
-
-
± 1
± 2
1 2 -l e a d E C G (i n cl u di n g Q T c F)
X
P K bl o o d s a m pl e
X m
L o c al t u m or a s s e s s m e nt ( R E CI S T) o, p
X
X
E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p p erf or m a n c e st at u s ; F U = f oll o w -u p; F/ W =  fr a cti o n p er w e e k; G y = Gr a y; 
HI V = h u m a n i m m u n o d efi ci e n c y vir u s; L 1 = L e si o n 1; L 2 = L e si o n 2; P D = p h ar m a c o d y n a mi c s; P K = p h ar m a c o ki n eti c s; Q T c F = Fri d eri ci a -c orr e ct e d Q T i nt er v al; 
R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s; R T = r a di ot h er a p y.
a.
T o b e gi v e n 1. 5 h o ur s ( ± 3 0 mi n ut e s) aft er d o si n g .
b.
F or l o gi sti c al r e a s o n s ( h a n dli n g a n d s e n di n g m at eri al s), D a y 1 m u st b e o n a W e d n e s d a y or e arli er.
c.
H e p atiti s B a n d C t e sti n g t o b e p erf or m e d at S cr e e ni n g u nl e s s o bt ai n e d wit hi n 3 m o nt h s pri or t o S cr e e ni n g. S cr e e ni n g f or HI V will b e p erf or m e d a c c or di n g 
t o l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
d.
H e art r at e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e, b o d y t e m p er at ur e, a n d b o d y w ei g ht.
e.
H ei g ht m e a s ur e d at S cr e e ni n g o nl y.
f.
Pr e d o s e vit al si g n s .
g.
L o c al t ol er a bilit y o nl y .
h.
S e e T a bl e 1 5 f or d et ail s of h e m at ol o g y t e st s.
i.
S e e  T a bl e 1 5 f or d et ail s of s er u m c h e mi str y t e st s.
j.
Uri n al y si s: di p sti c k f oll o w e d b y mi cr o s c o pi c e x a mi n ati o n if a b n or m al r e s ult s .
m.
P K s a m pl e s will b e c oll e ct e d a s d e s cri b e d i n  T a bl e 9 . S a m pli n g s c h e d ul e m a y b e c h a n g e d i n t h e c o ur s e of t h e tri al. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 4 9
o.
L o c al t u m or a s s e s s m e nt (i n irr a di at e d l e si o n s) b y cli ni c al e x a m or i m a gi n g a c c or di n g t o R E CI S T v 1. 1. B a s eli n e t u m or e v al u ati o n c a n b e u p t o 2 1 d a y s ol d 
w h e n tr e at m e nt st art s.
p.
O nl y a p pli c a bl e f or a d diti o n al c o h ort s wit h M 3 8 1 4 
 f or m ul ati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 4 9
T a ble 8
R a di ot her a p y ( A l o ne) a n d M 3 8 1 4
+ R T Sc he d ule f or t he A ncill ar y 
C li nic al P r o of - of- Pri nci ple (c P o P) P art of t he Tri al
D a y 1 ( b a s eli n e) a
D a y 1
D a y 2
L e si o n 1
Bi o p s y
B 1
B 3 b
--
R T c
--
+
--
M 3 8 1 4
--
-
--
L e si o n 2
Bi o p s y
B 2
--
B 4 b
R T c
--
--
+
M 3 8 1 4
--
--
+
R T = r a di ot h er a p y .
a.
B a s eli n e bi o p s y t o b e t a k e n a n y ti m e pri or t o R T f or b ot h l e si o n s ( S cr e e ni n g t o D a y 1).
b.
C or e bi o p s y n e e d s t o b e p erf or m e d 2 t o 4 h o ur s aft er R T. D et ail e d ti m e s c h e d ul e a n d s a m pl e c oll e cti o n 
pr o c e d ur e s will b e d e s cri b e d i n t h e l a b or at or y m a n u al .
c.
R a di ot h er a p y will b e gi v e n a s a si n gl e hi g h d o s e of R T ( 1 0- 2 5 G y) . T h e d o s e of M 3 8 1 4
s h o ul d b e 
a d mi ni st er e d 1. 5 h o ur s ( ± 3 0 mi n ut e s) b ef or e r a di ot h er a p y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 4 9
T a ble 9
P h ar m ac o ki netic a n d 
 S a m pli n g Sc he d ule of M 3 8 1 4
d uri n g P h ase I a, P h ase I b , a n d t he A ncill ar y c P o P P a rt of t he Tri al
Ti m e p oi nt s
V ol u m e of 
bl o o d r e q uir e d 
p er ti m e p oi nt a
P h a s e I a
P h a s e I b b
A n cill ar y  c P o P
P K c
2 m L 
P K c
2 m L
P K c
2 m L
F D 1
Pr e d o s e
X
X
H 0. 5
X
X
H 1. 0
X
R T
1 . 5 h o ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
1 0 -2 5
H 2. 0
X
X
H 4 . 0
X
X
H 6. 0
X
X
F D 2
Pr e d o s e d
X
X
H 0. 5
X
H 1. 0
X
R T
1 . 5 ho ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
1 0 -2 5
H 2. 0
X
H 4. 0
X
F D 6
Pr e d o s e d
X
H 0. 5 g
X
H 1. 0 g
X
R T
1. 5 h o ur s 
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
H 2. 0 g
X
H 4. 0 g
X
H 6. 0 g
X
F D 7 g
Pr e d o s e d
X
F D 1 0 f
Pr e d o s e d
X
X
H 0. 5
X
X
H 1. 0
X
R T
1 . 5 h o ur s
( ± 3 0 mi n ut e s) 
aft er d o si n g
3 G y x 1 0; 5 
2 G y x 3 3 -3 5 ; 
2 G y x 3 3 ; 5 
2 G y x 3 3 -3 5 ; 5
H 2. 0
X
X
H 4. 0
X
X
c P o P = cli ni c al pr o of -of -pri n ci pl e; F D = fr a cti o n d a y; F/ W = fr a cti o n p er w e e k; G y = G r a y; N S C L C = n o n -s m all c ell l u n g 
c a n c er;
; P K = p h ar m a c o ki n eti c; R T = r a di ot h er a p y; S C C H N = s q u a m o u s c ell c ar ci n o m a 
h e a d a n d n e c k; S M C = S af et y M o nit ori n g C o m mitt e e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C
C CI
C CI
C CI








M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 4 9
M 3 8 1 4
als o tar gets PI 3 K , s pecifically t he delta is of or m, at a c o nce ntrati o n 1 5 5 -f ol d hi g her t ha n 
t hat nee de d t o o btai n a n i n hi biti o n of D N A -P K. T he c o nce ntrati o ns necessar y t o i n hi bit t he vari o us 
ot her PI 3 K is of or ms are 4 0 0 - 5 0 0 ti mes hi g her t ha n t hat nee de d t o i n hi bit D N A -P K. O ne a d diti o nal 
k n o w n off -tar get of i nterest is affecte d by M 3 8 1 4 , h u ma n c ycl o -o x y ge nase, wit h a 5 0 % i n hi bit or y  
c o nce ntrati o n of 1. 7 µ M.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 4 9
3. 1. 2
F or m ul ati o n De vel o p me nt
A p o w d er i n ca ps ule ( P i C) f or m ulati o n is use d i n t his trial; t hese ca ps ules are fille d wit h b ul k dr u g 
s u bsta nce a n d d o n ot c o ntai n a n y  exci pie n ts. H o we ver, the pr o d ucti o n pr ocess f or t he ca ps ules is 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 4 9
n ot easil y s ustai na ble f or st u dies wit h a hi g h n u m ber of s u bjects. T he dr u g pr o d uct t hat is g oi n g t o 
be use d f or P hase II s h o ul d be a f or m ulati o n ma n ufact ure d wit h acce pta ble scale-u p a bilit y  of t he 
p har mace utical pr ocess t o easil y su p pl y P hase II trials. T heref ore , fil m-c oate d 
 ta blets ha ve 
bee n de vel o pe d a n d are g oi n g t o be i n vesti gate d i n t his trial.
3. 2
Tri al P o p ul ati o n
T he trial p o p ulati o n i n P hase Ia, Ar m A, c o nsists of pre vi o usl y treate d s u bjects dia g n ose d wit h 
l ocall y a d va nce d disease (a ny t u m or i ncl u di n g l y m p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n
or t h ora x t hat is n ot a me na ble t o s ur gical t hera py wit h a n i n dicati o n f or palliati ve R T ( 3 0 G y  in 
1 0 fracti o ns). P hase I a, Ar m B, c o nsists of s u bjects wit h treat me nt-naï ve s q ua m o us cell carci n o ma 
hea d a n d nec k (S C C H N ) eli gi ble f or a c o urse of c urati vel y i nte n de d R T ( 6 6 t o 7 0 G y  in 3 3 t o 
3 5 fracti o ns) wit h c o nc urre nt cis plati n. I n t he P hase I b part, t he trial p o p ulati o n is treat me nt-naï ve 
s u bjects wit h n o n- s mall cell l u n g ca ncer (N S C L C ) Sta ge III A/ B ( n ot eli gi ble f or s ur gical resecti o n 
or c o nc urre nt c he m ora diati o n) eli gi ble f or a c o urse of c urati vel y i nte n de d R T
( 6 6 G y  in 
3 3 fracti o ns) ( Ar m A) ; a f urt her trial p o p ulati o n of S C C H N s u bjects, as s pecifie d f or Ar m B i n 
P hase I a a n d usi n g t he sa me c he m ora di ot hera p y  ( C R T) re gi me n, will be i ncl u de d ( Ar m B) .
I n t he a ncillar y c P o P part of t he trial, t he trial p o p ulati o n is s u bjects wit h at least t w o
(s u b)c uta ne o us t u m or/ metastases of a ny t y p e (at least 2 c m a part) wit h a n i n dicati o n f or hi g h d ose 
palliati ve R T ( 1 0-2 5 G y  i n o ne fracti o n).
3. 3
R ati o n ale f or Tri al Desi g n a n d J ustific ati o n of St arti n g D ose
T his trial is desi g ne d i n t w o se q ue ntial parts, a n d i ncl u des o ne a ncillar y c P o P part t hat will r u n i n 
parallel wit h t he P hase I a/Ib c ore trial. T h us, t he o verall trial has 5 mai n parts (Fi g ure 1) . P hase Ia 
Ar m A
will e val uate t he safety a n d t olera bility of M 3 8 1 4
i n c o m bi nati o n wit h fracti o nate d 
palliati ve R T i n all-c o mers wit h l ocall y ad va nce d t u m ors or metastases l ocalize d i n t he hea d a n d 
nec k re gi o n or t h ora x. P hase Ia Ar m B will e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n 
c o m bi nati o n wit h fracti o nate d c urati vel y i nte n de d R T i n c o m bi nati o n wit h c o nc urre nt cis plati n i n 
s u bjects wit h treat me nt-naï ve l ocal/l ocall y  a d va nce d S C C H N. T he P hase I b part will e val uate t he 
safety a nd o verall res p o nse of M 3 8 1 4
i n c o m bi nati o n wit h fracti o nate d c urati vel y i nte n de d R T i n 
s u bjects wit h Sta ge III A/ B N S C L C a n d t he safety a n d o verall res p o nse of M 3 8 1 4
i n c o m bi nati o n 
wit h fracti o nate d c urati vel y inte n de d R T wit h c o nc urre nt cis plati n i n s u bjects wit h l ocal/l ocall y 
a d va nce d S C C H N. T he a ncillar y c P o P part of t he trial will be c o n d ucte d i n parallel wit h t he P hase 
Ia/I b c ore trial t o e x pl ore t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n tar get e n ga ge me nt 
i n t u m or tiss ue.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 4 9
3. 4
R ati o n ale f or R a di ot her a p y D ose
T he R T d oses pr o p ose d f or t he P hase Ia (Ar m A: 3 G y  x 10; 5 fracti o ns per wee k [ F/ W] a n d 
Ar m B: 2 G y  x 3 3 t o 3 5 ; 5 F/ W ) a n d P hase I b (2 G y  x 33; 5 F/ W [ N S C LC] a n d 2 G y  x 3 3 t o 3 5;
5 F/ W [ S C C H N] ) are Sta n dar d of Care ( S o C) f or palliati ve a n d c urati ve i nte n de d ra di ot hera p y i n 
t he s pecifie d areas of t he b o d y . I n t he a ncillar y c P o P part of t he trial (si n gle d ose 1 0- 2 5 G y ) t he 
l o wer li mit of 1 0 G y is set as t his is t he t hres h ol d t hat nee ds t o be gi ve n bef ore we ca n detect t he 
p har mac o d y n a mics si g nal. T he ra n ge of 1 0 t o 2 5 G y is als o t he S o C w he n hi g h d ose ra di ot hera p y 
is gi ve n as a si n gle s h ot.
3. 5
R ati o n ale f or Cis pl ati n D ose
T he d ose of cis plati n pr o p ose d f or P hase Ia, Ar m B a n d P hase I b, e x pa nsi o n c o h ort f or Ar m B 
( S C C H N) is 1 0 0 m g/ m 2 gi ve n t wice ( o n F D 1 a n d F D 3 1), or 4 0 m g/ m 2 gi ve n wee kl y, c o nc urre ntl y 
wit h R T. T he d oses are i n li ne wit h c urre nt me dical g ui deli nes ( Nati o nal C o m pre he nsi ve Ca ncer 
Ne t w or k, A merica n C olle ge of C hest P h y sicia ns/A merica n S ociet y o f Cli nical O nc ol o g y [ A S C O], 
a n d E ur o pea n S ociet y  for Me dical O nc ol o g y ) wit h refere nce t o t he S o C f or c o nc urre nt C R T wit h 
cis plati n i n t he treat me nt of s u bjects wit h S C C H N.
3. 6
K n o w n a n d P ote nti al Ris ks a n d Be nefits t o H u m a n S u bjects
T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he I CH E 6 G C P G ui da nce,
a n d a n y 
a d diti o nal a p plica ble re g ulat or y re q uire me nts.
T he be nefit -ris k relati o ns hi p has bee n caref ull y co nsi dere d i n t he pla n ni n g of t he trial. Base d o n 
t he 
data o n M 3 8 1 4
a n d o n p u blis he d n o n cli nical a n d cli nical data s h o wi n g e vi de nce of 
cell deat h a n d t u m or s hri n ka ge after si n gle-a ge nt use i n t u m ors wit h pre -e xisti n g altere d re pair 
mec ha nis ms, t h us ill ustrati n g t he c o nce pt of s ynt hetic let halit y, t he c o n d uct of t his trial is 
c o nsi dere d j ustifia ble usi n g t he d ose(s) a n d d osa ge re gi me n(s) of t he I MP as s pecifie d i n t his 
cli nical trial pr ot oc ol [ 1, 2, 3].
It is k n o w n t hat R T ca n ca use ac ute t o xicities i n t he f or m of, f or e xa m ple, ra diati o n der matitis a n d 
m uc ositis. Defi niti ve c o nc urre nt C R T, c o nsi dere d t he S o C f or i n o pera ble l oc ore gi o nally a d va nce d 
S C C H N, is ass ociate d wit h si g nifica nt ac ute t o xicities i ncl u di n g st o matitis ( oral m uc ositis), 
s wall o wi n g dys f u ncti o n ( o d yn o p ha gia, d y s pha gia), decrease d a p petite, a n d der matitis [4, 5, 6, 7] .
F or i nc ura ble hea d a n d nec k ca ncers, R T has bee n de m o nstrate d t o be a n effecti ve palliati ve 
m o dalit y  an d m ost ac ute t o xicities are ge nerall y relate d t o m uc osal i nfla m mati o n a n d der matitis, 
e ve n t h o u g h t he se verit y an d fre q ue nc y of t hese A Es were l o wer c o m pare d wit h C R T i n t he 
c urati ve setti n g [ 8]. Late t o xicities arisi n g 3 m o nt hs or later after t he e n d of R T ca n be see n i n t he
f or m of, f or e xa m ple, xer ost o mia, es o p ha gitis, p ne u m o nitis, a n d fi br osis. Patie nts s h o ul d be 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 4 9
re mi n de d t o c o ntact t he trial site i m me diatel y in case of t o xicities w here t he y will be e val uate d a n d 
treate d as a p pr o priate acc or di n g t o i nstit uti o nal g ui deli nes . P ote ntiall y  ac ute a n d late t o xicities ca n 
be m ore se vere w he n R T is gi ve n i n c o m bi nati o n wit h M 3 8 1 4.
T his will be e val uate d o n a n 
o n g oi n g basis f or u p t o 1 2 m o nt hs after t he e n d of treat me nt .
I n this trial, t he S M C will m o nit or t he be nefit -ris k rati o o n a n o n g oi n g basis . The trial will b e 
disc o nti n ue d i n t he e ve nt of a n y ne w fi n di n gs t hat i n dicate a rele va nt deteri orati o n of t he 
be nefit -ris k rati o f or t he s u bjects, w hic h w o ul d re n der c o nti n uati o n of t he trial u nj ustifia ble.
Base d o n t he a vaila ble 
 a n d cli nical data t o date, t he c o n d uct of t he trial s pecifie d i n 
t his pr ot oc ol is c o nsi dere d j ustifia ble i n s u bjects wit h l ocall y  a d va nce d disease. 
4
Tri al O bjecti ves
4. 1
Pri m ar y O bjecti ves
T he pri mar y  o bjecti ves of t he trial are:

P hase Ia ( d ose escalati o n): 
o
( Ar m A) T o deter mi ne t he ma xi m u m t olerate d d ose (M T D)
a n d a R P 2 D f or M 3 8 1 4
i n 
c o m bi nati o n wit h fracti o nate d palliati ve R T f or t u m ors or metastases l ocalize d i n t he hea d 
a n d nec k re gi o n or t h ora x ( 3 G y x 1 0; 5 F/ W).
o
( Ar m B) T o deter mi ne t he M T D a n d a R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h c urati vel y 
i nte n de d C R T ( 2 G y  x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt cis plati n) i n treat me nt-naï ve
s u bjects wit h l ocal/l ocall y a d va nce d S C C H N .

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
( Ar m A) T o
e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h 
fracti o nate d R T
( 2 G y  x 3 3 ; 5 F/ W) i n treat me nt-naï ve s u bjects wit h S ta ge III A/ B 
N S C L C n ot eli gi ble f or c o nc urre nt c he m ora diati o n
o
( Ar m B) T o e val uate t he safety a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h C R T
( 2 G y x 3 3 t o 3 5; 5 F/ W wit h c o nc urre nt cis plati n) i n s u bjects wit h treat me nt-naï ve
S C C H N .
4. 2
Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ves of t he trial are:

P hase Ia ( d ose escalati o n): 
o
T o e val uate t he safety pr ofile a n d t olera bilit y of M 3 8 1 4
i n c o m bi nati o n wit h palliati ve 
R T f or t u m ors or metastases l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x ( Ar m A) a n d 
i n c o m bi nati o n wit h c urati vel y inte n de d C R T i n treat me nt-naï ve s u bjects wit h S C C H N
( Ar m B)
o
T o e x pl ore t he a ntit u m or acti vit y of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) a n d C R T
( Ar m B).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 4 9

P hase I b ( disease s pecific c o h ort e x pa nsi o n): 
o
T o e x pl ore t he efficac y i n ter ms of o verall res p o nse rate, pr o gressi o n -free s ur vi val ( P F S) 
a n d o verall s ur vi val ( O S) of M 3 8 1 4
i n c o m bi nati o n wit h R T ( Ar m A) or i n c o m bi nati o n 
wit h C R T ( Ar m B) , a n d l ocal/l ocal re gi o nal t u m or c o ntr ol ( Ar m B)

P hase Ia , P hase I b, a n d a ncillar y c P o P parts : T o assess t he P K of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 4 9
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a c o m bi ne d P hase Ia/I b, o pe n la bel, d ose escalati o n, a n d d ose e x pa nsi o n trial desi g ne d t o 
e x pl ore t he sa fet y, t olera bilit y, P K a n d P D pr ofile, a n d cli nical acti vit y of M 3 8 1 4 i n c o m bi nati o n 
wit h R T / C R T, a n d t o deter mi ne t he M T D a n d R P 2 D f or M 3 8 1 4
i n c o m bi nati o n wit h R T / C R T. A n 
a ncillar y cP o P part of t he trial will be c o n d ucte d i n parallel wit h t he P hase Ia/I b c ore trial t o e x pl ore 
t he P D effect of M 3 8 1 4
i n c o m bi nati o n wit h R T o n tar get e n ga ge me nt i n t u m or tiss ue.
I n t he P hase Ia part of t he trial, pre vi o usl y treate d s u bjects wit h l ocally a d va nce d disease (a ny 
t u m or or metastas es i ncl u di n g ly m p h o mas) l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x t hat is 
n ot a me na ble t o s ur gical t hera p y, or wit h sta n dar d s yste mic t hera p y wit h a n i n dicati o n f or 
palliati ve R T ( 3 0 G y i n 1 0 fracti o ns) will be i ncl u de d i n Ar m A. After t he first d ose le vel ( 1 0 0 m g 
M 3 8 1 4 ) i n Ar m A has bee n c o m plete d, a sec o n d d ose escalati o n ar m ( Ar m B) will be i nitiate d at 
a starti n g d ose of 5 0 m g M 3 8 1 4
i n treat me nt-naï ve s u bjects wit h S C C H N, w h o are eli gi ble f or 
fracti o nate d R T (6 6 t o 7 0 G y  i n 3 3 t o 3 5 fracti o ns) wit h c o nc urre nt cis plati n. I n t he P hase I b part, 
eac h ar m fr o m P hase Ia will ha ve a n e x pa nsi o n c o h ort. After esta blis h me nt of R P 2 D i n Ar m A, 
s u bjects wit h treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n or
c o nc urre nt c he m ora diati o n will be gi ve n M 3 8 1 4
i n c o mbi nati o n wit h R T ( 6 6 G y  in 3 3 fracti o ns)
i n t he Ar m A e x pa nsi o n c o h ort. T he e x pa nsi o n c o h ort f or Ar m B will i ncl u de treat me nt-naï ve
s u bjects wit h S C C H N, as s pecifie d i n P hase Ia a n d will be gi ve n t he sa me C R T ( 6 6 t o 7 0 G y i n 3 3 
t o 3 5 fracti o ns wit h c o nc urre nt cis plati n) i n c o m bi nati o n wit h M 3 8 1 4
at t he R P 2 D esta blis he d i n 
P hase Ia Ar m B. I n t he a ncillar y c P o P part of t he trial, s u bjects wit h at least 2 (s u b)c uta ne o us 
t u m or/ metastases of a n y t y p e (at least 2 c m a part) wit h a n i n dicati o n f or si n gle hi g h d ose palliati ve 
R T will be i ncl u de d.
A sc he matic of t he o verall trial desi g n is s h o w n i n Fi g ure 1,  t he d ose escalati o n is s h o w n i n 
Fi g ure 2 a n d t he treat me nt o ver vie w wit h t he ta ble ts i n P hase Ia Ar m A is s h o w n i n  Fi g ure 3 . T he 
Sc he d ule of Assess me nt s is s h o w n f or the P hase Ia part of t he trial i n Ta ble 1 ( Ar m A - ca ps ule), 
Ta ble 2 ( Ar m A – ta blet), a n d Ta ble 5 ( Ar m B, S C C H N c o h ort), f or t he first 3 s u bjects i n t he
P hase I b part of t he trial (Ar m A , N S C L C c o h ort) i n Ta ble 3,  f or t he P hase I b part of t he trial i n
Ta ble 4 (Ar m A , N S C L C c o h ort) a n d Ta ble 6 (Ar m B, S C C H N c o h ort), a n d t he a ncillar y c P o P
part of t he trial i n Ta ble 7 . In a d diti o n, t he sc he d ule of trial treat me nt a n d bi o psies i n t he a ncillar y
c P o P part of t he trial are o utli ne d i n Ta ble 8.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 4 9
Fi g ure 1
O ver vie w of T ri al D esi g n wit h 5 S e g me nts
ci s = ci s pl ati n; c P o P = cli ni c al pr o of- of -pri n ci pl e; C R T = c h e m or a di ot h er a p y; G y = gr a y;  
 = 
 
N S C L C = n o n - s m all c ell l u n g c a n c er; R T = r a di ot h er a p y; S C C H N = S q u a m o u s c ell c ar ci n o m a h e a d a n d n e c k .
Ar m  A / P h a s e Ia p art
A n y t um o r or m et a st a s e s i n  
h e a d , n e c k  or t hor a x  3 G y
× 1 0
•
D o s e e s c al ati o n  in 
p a lliati v e s etti n g
•
 f or mul a ti o n to b e 
i ntr o du c e d
Ar m  A / P h a s e I b p art
N S C L C III A/ B
•
2 G y × 3 3 E x p a n s i o n   
c o h o rt f or R T co m bi n a ti o n
•
E s t a blis h  saf et y pr ofil e of 
c o m b i nati o n  in p a ti e nt s n o t 
el i gi bl e for c o n c u rr e nt 
c h e m or a d i ati o n
Ar m B / P h a s e I a p ar t
tr e at me n t-n a ï ve S C C H N
2 G y × 3 3 t o 3 5 + ci s
•
D o s e e s c al ati o n  in c u r ati ve 
s etti n g,  ini ti at e d i n US o n l y
•
C R T  wit h Ci s pl ati n
Ar m  B / P h a s e I b p ar t
tr e at me n t-n a ï v e S C C H N
2 G y × 3 3 t o 3 5 + ci s
•
E x p a n s i o n co h ort f or C R T 
c o m b i nati o n
A n ci ll ar y c P o P p art of t h e tr i al
S u bj e ct s wi t h at le a st t w o c ut a n e o u s t um o r s or m et a st a s e s. Pr e a n d 
p o st tr e at me n t bi o p si e s t a k e n  to e v al u a t e o n tar g et m o d ul a ti o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 4 9
Fi g ure 3
Tre at me nt O ver vie w ( P h ase I a Ar m A )
D L T = d o s e li miti n g t o xi cit y; F D = fr a cti o n d a y; G y = gr a y; R T = r a di ot h er a p y.
N ot e: t h e st arti n g d o s e f or t h e t a bl et i s 5 0 % of t h e c urr e nt t ol er a bl e c a p s ul e f or m ul ati o n.
Scree ni n g Per i o d
After pr o vi di n g i nf or me d c o nse nt f or t he trial a n d t he P G x a nal ysis, t he eli gi bilit y of trial s u bjects 
will be esta blis he d acc or di n g t o t he pr ot oc ol -defi ne d incl usi o n ( Secti o n 5. 3. 1 ) a n d excl usi o n 
criteria (Secti o n 5. 3. 2 ) d uri n g a ma xi m u m 2 1 -da y  Scree ni n g Peri o d (scree ni n g a n d baseli ne 
e val uati o n s). O nce all scree ni n g pr oce d ures ha ve bee n c o m plete d a n d it has bee n c o nfir me d t hat a 
s u bject meets all t he eli gi bilit y criteria, t he s u bject will be e nr olle d i nt o t he trial a n d e nter t he 
treat me nt p eri o d. 
Tre at me nt Peri o ds
I n t he P hase Ia part ( Ar ms A a n d B) , su bjects will be assi g ne d t o a d ose deter mi ne d b y  the S M C 
i n t he ne xt a vaila ble o pe n treat me nt c o h ort g ui de d b y  a Ba yesia n l o gistic re gressi o n m o del wit h 
o ver d ose c o ntr ol. O nl y  escalati o n i n t he ta blet c o h ort of Ar m A will be perf or me d acc or di n g t o a 
3 + 3 desi g n as it is n ot pla n ne d t o deter mi ne M T D, b ut rat her c o nfir m t he R P 2 D of t he ca ps ule 
f or m ulati o n. F ull details of t he d osi n g re gi me ns f or M 3 8 1 4
are pr o vi de d i n Secti o n 6. 3. All 
treat me nt wit h M 3 8 1 4
will be gi ve n i n c o m bi nati o n wit h R T o nl y i n Ar m A, a n d i n c o m bi nati o n 
wit h C R T i n Ar m B .
T hr o u g h o ut t he treat me nt peri o d , s u bjects i n all c o h orts will atte n d re g ular trial visits f or d osi n g, 
safety e val uati o ns a n d bl o o d sa m pli n g f or P K a n d P D , as descri be d i n Secti o n 7.
P hase Ia 
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, s u bjects i ncl u de d i n t he P hase Ia, 
Ar m A, part of t he trial will recei ve treat me nt wit h M 3 8 1 4
at a starti n g d ose of 1 0 0 m g  QD f or 
2 c o nsec uti ve wee ks d uri n g t he peri o d R T ( 3 G y x 1 0, 5 F/ W) is gi ve n. T he a d mi nistrati o n of 
M 3 8 1 4
will ta ke place 1 . 5 h o urs ( ± 3 0 mi n utes) bef ore t he start of R T.
I n Ar m A, the s u bjects i n t he d ose escalati o n part will recei ve t he ca ps ule f or m ulati o n of M 3 8 1 4 
t hr o u g h o ut, e xce pt f or t he s u bjects i n t he ta blet testi n g c o h orts , w h o
will recei ve t he ca ps ule 
DL T p eri o d
Tr e at m e nt a d mi nistr ati o n
( M 3 8 1 4 + 3 G y R T)
Tr i al d a y
1 2 3 4 5 6 7 8
1 5
2 2 
2 9
s af ety f oll o w-u p
Fr acti o n d a y ( F D)
1 2 3 4 5 
6 7 8 9 1 0
Tr i al w e e k
1
2 
3 
4 
5
t a bl et
c a ps ul e
Ta bl e t t esti n g c o h orts
t a bl et
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI




M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 4 9
It is pla n ne d t o e nr oll 1 1 s u bjects wit h (s u b)c uta ne o us t u m or/metastases i n t he a ncillar y c P o P part 
of t he trial usi n g M 3 8 1 4 
ca ps ule f or m ulati o n a n d a p pr o xi matel y 12 a d diti o nal s u bjects wit h 
(s u b)c uta ne o us t u m or/ metastases usi n g M 3 8 1 4 
 f or m ulati o n.
F oll o w -u p Peri o ds
P hase Ia /Ib
T he f oll o w- u p peri o d f or all s u bjects i n t he P hase Ia a n d I b part s of t he trial will c o nsist of t he 
f oll o wi n g: 

D L T Peri o d : A 5- wee k ( Ar m A) or 1 2- wee k ( Ar m B) D L T p eri o d after t he first d ose of M 3 8 1 4
f or t he e val uati o n of ‘ac ute’ s yste mic a n d l ocal t o xicit y i n all s u bjects i n P hase Ia a n d a 1 2- wee k 
D L T peri o d after t he first d ose of M 3 8 1 4
i n t he first 3 s u bjects of t he safet y ru n- i n part i n t he 
N S C L C e x pa nsi o n c o h ort d uri n g P hase I b ( Ar m A)

S h ort -ter m Safet y F oll o w -u p: A f oll o w- u p f or a peri o d of 3 0 d a y s after t he e n d of R T f or 
e val uati o n of safet y

Mi d -ter m Safety F oll o w - u p: A safet y f oll o w -u p peri o d of 3 m o nt hs after e n d of R T t o e val uate 
si g ns of R T-i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

L o n g -ter m Safet y F oll o w - u p: A safety f oll o w-u p peri o d u ntil 1 2 m o nt hs
after e n d of R T t o 
e val uate late si g ns of R T -i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues

S ur vi val F oll o w - u p: A f oll o w -u p peri o d t hat will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T/ C R T.
A ncillar y  c P o P part
S u bject o verall safety will be e val uate d u p t o Da y 1 0 ( F oll o w- u p Peri o d) . L ocal t olera bilit y  will 
be re p orte d o n D a y s 1 0 a n d 3 2 ( D a y s 8 a n d 3 0 after t he e n d of treat me nt, Safet y  Foll o w -u p Peri o d) . 
I n a d diti o n, o n Da y 1 0 l ocal t u m or res p o nse will be assesse d i n irra diate d lesi o ns ( o nl y a p plica ble
f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 f or m ulati o n]). S u bjects will be per mitte d t o recei ve a n y 
i n dicate d s yste mic t hera pe utic m o dalit y as s o o n as cli nicall y i n dicate d after Da y 1 0.
5. 1. 1
D ose E sc al ati o n Rules
T he criteria f or d ose escalati o n are base d o n t he occ urre nce of A Es a n d/ or D L Ts t hat are u nrelate d 
t o u n derl y i n g c o n diti o ns a n d/ or t o c o nc o mita nt me dicati o n d uri n g t he D L T peri o d i n e val ua ble 
s u bjects i n eac h c o h ort. T he D L T wi n d o w of 5 wee ks (P hase Ia, Ar m A) or 1 2 wee ks (P hase Ia, 
Ar m B a n d t he first 3 s u bjects i n t he e x pa nsi o n c o h ort f or Ar m A [ N S C L C]) after t he start of 
M 3 8 1 4 treat me nt all o ws a n e val uati o n of ac ute t o xicit y. M 3 8 1 4
d ose escalati o n will n ot pr ocee d 
t o t he ne xt d ose le vel u ntil all s u bjects i n t he pre vi o us d ose le vel ha ve bee n o bser ve d f or t he 
d urati o n of t he D L T peri o d . H o we ver, R T / C R T a n d t he c o m bi nati o n of R T / C R T a n d M 3 8 1 4
ca n 
als o gi ve rise t o later t o xicities. A 3- m o nt h mi d -ter m safet y f oll o w-u p will be perf or me d i n all 
s u bjects i n t he Phase Ia part of t he trial a n d, o nce a vaila ble, t hese data will als o g ui de s u bse q ue nt 
d ose escalati o n a n d t he esta blis h me nt of t he R P 2 D. A vaila ble P K a n d P D data will als o be ta ke n 
i nt o c o nsi derati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 4 9
D ose Esc al ati o n D uri n g P h ase I a
A Ba yesia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose c o ntr ol will be use d t o assist 
t he S M C wit h d ose selecti o n d uri n g t he P hase Ia d ose escalati o n (ca ps ule f or m ulati o n i n Ar m A/ B, 
a n d ta blet f or m ulati o n i n Ar m B) . C o h orts of 3 s u bjects eac h will be treate d at t he sa me d ose le vel 
(ca ps ule starti n g d ose: 1 0 0 m g Q D f or Ar m A a n d 5 0 m g Q D f or Ar m B). T he m o del i nc or p orates 
pri or i nf or mati o n (fr o m n o n cli nical data) a n d o bser ve d i nf or mati o n fr o m eac h c o m plete d c o h ort 
(a n d data fr o m all pre vi o us c o h orts) t o pr o vi de a rec o m me n de d d ose f or t he ne xt c o h ort. A 
preselecte d set of acce pta ble d oses are c o nsi dere d b y t he m o del, h o we ver d oses w hic h are n ot part 
of t he pres pecifie d set ma y  be c h ose n as well . T he m o del e ns ures t hat rec o m me n de d d oses 
c orres p o n d t o a pr o ba bilit y  of less t ha n 2 5 % t hat t he tr ue D L T rate is m ore t ha n 3 5 % i n Ar m A 
a n d 4 5 % i n Ar m B . D ose escalati o n will st o p i n eac h ar m as s o o n as t he first of t he f oll o wi n g 
st o p pi n g r ules a p pl y: a ma xi m u m of 3 0 s u bjects are i ncl u de d, m ore t ha n t hree c o h orts are assi g ne d 
t o t he sa me d ose le vel, or t he esti mate of D L T pr o ba bilit y  at t he M T D reac hes a s ufficie nt precisi o n
(see Secti o n 8 f or m ore details).
Selecti o n of t he R P 2 D deter mi ne d wit h t he ca ps ule f or m ulati o n will be perf or me d i n P hase Ia Ar m 
A base d o n t he a vaila ble cli nical i nf or mati o n alrea d y ge nerate d wit h t he M 3 8 1 4 
ca ps ule at 
escalati n g d oses. T heref ore, it is a ntici pate d t hat a s maller n u m ber of d ose c oh orts a n d s u bjects 
will be re q uire d t o reassess safety, t olera bilit y an d P K of M 3 8 1 4 after d osi n g wit h t he ta blet 
f or m ulati o n i n c o m bi nati o n wit h R T b y  use of sta n dar d 3 + 3 d ose escalati o n desi g n criteria (see 
S ecti o n 5. 1. 2 f or m ore details). 
D ose Esc al ati o n D uri n g P h ase I b
F oll o wi n g c o m pleti o n of t he scree ni n g a n d baseli ne e val uati o ns, treat me nt-naï ve s u bjects wit h 
S ta ge III A/ B N S C L C e nr olle d i n t he P hase I b part of t he trial ( Ar m A e x pa nsi o n c o h ort) will 
recei ve M 3 8 1 4 , t o be gi ve n 1. 5 h o urs ( ± 3 0 mi n utes) bef ore eac h R T fracti o n f or 3 3 fracti o ns. T he 
d ose of M 3 8 1 4
f or t he first 3 s u bjects will be esta blis he d fr o m t he a vaila ble data i n b ot h ar ms of 
the P hase Ia part of t he trial . I n cas e a R P 2 D i n A r m B has bee n esta blis he d bef ore a R P 2 D fr o m 
Ar m A, t he n t he Ar m A e x pa nsi o n c o h ort ca n be i nitiate d at t he R P 2 D i de ntifie d i n Ar m B. I n case 
a R P 2 D has bee n esta blis he d first i n Ar m A, t he first 3 s u bjects will be treate d o ne d ose le vel bel o w 
t he R P 2 D. Base d o n t he safety pr ofile, t he S M C will deci de if t he d ose ca n be escalate d t o t he 
R P 2 D i de ntifie d i n P hase Ia, Ar m A. 
T he d ose i n t he Ar m B e x pa nsi o n c o h ort will be t he deter mi ne d R P 2 D of M 3 8 1 4
fr o m P hase Ia 
Ar m B a n d will be gi ve n t o s u bjects wit h treat me nt-naï ve S C C H N i n c o m bi nati o n wit h t he sa me 
C R T re gi me n as i n P hase Ia ( Ar m B).
D oses of M 3 8 1 4
i n t he A ncill ar y c P o P P art of t he Tri al
I n the a ncillar y c P o P part of t he trial, t he d oses are fi xe d at 1 0 0 m g , 2 0 0 m g, a n d 4 0 0 m g . After 
t he t hree pla n ne d c o h orts, a d diti o nal c o h ort(s) mi g ht be o pe ne d u p o n S M C decisi o n.
T he si n gle d ose of M 3 8 1 4
t o be a d mi nistere d o n Da y  2 of t he a ncillar y c P oP part of t he trial is 
fi xe d f or s uccessi ve c o h orts as s h o wn i n Ta ble 1 2.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI








M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 4 9
t o xicities at eac h ne w d ose. T he S M C ma y deci de t o sto p d ose escalati o n at a n y d ose le vel base d 
o n safety a n d P K data.
I ntr o d ucti o n a n d e val uati o n of t he ta blet will be perf or me d i n t he P hase Ia, Ar m A part of t he trial. 
A first c o h ort of patie nts will recei ve t he ta blet f or m ulati o n at a d ose of 1 0 0 m g. Base d o n t he 
pre vi o us cli nical e x perie nce wit h t he M 3 8 1 4 ca ps ule d oses u p t o 4 0 0 m g i n t he o n g oi n g d ose 
escalati o n, a n d t he a ntici pate d ma xi mal e x p os ure after a d mi nistrati o n of t he ta blet, t he i nitial ta blet 
d ose of 1 0 0 m g i n t he first ta blet c o h ort is e x pecte d t o be safe a n d well -t olerate d.
After re vie w of t he safety, t olera bilit y, a n d P K data fr o m t his c o h ort i n relati o n t o t he data o btai ne d 
i n t he o n g oi n g d ose escalati o n, t he S M C ma y  deci de t o test f urt her ta blet d ose le vels. T he ai m is 
t o c o nfir m t he R P 2 D t hat has bee n defi ne d f or t he ca ps ule, usi n g t he ta blet f or m ulati o n. 
T he desi g n of t he ta blet testi n g c o h orts i n t he P hase Ia part of Ar m A als o i ncl u des i ntra-i n di vi d ual 
c o m paris o n of si n gle d ose P K of M 3 8 1 4 after a d mi nistrati o n of t he ta blet vers us ca ps ule. T he 
ca ps ule a d mi nistere d o n F D 6 after a 4 8- h o ur was h -o ut is n o t e x pecte d t o be i nfl ue nce d b y  th e 
pre vi o us a d mi nistrati o n of M 3 8 1 4 ta blets o n F D 1 t o F D 5, c o nsi deri n g t he me dia n ter mi nal half -life 
of 5. 5 h o urs (ra n ge 2. 0 t o 8. 8 h o urs, preli mi nar y data esti mate d i n t he 
) 
after m ulti ple dail y  dosi n g. Cli nical safety, t olera bilit y , a n d P K res ults o btai ne d i n P hase Ia Ar m A 
will deter mi ne s u bse q ue nt i ntr o d ucti o n of t he ta blet i n ot her parts of t he trial.
5. 2. 1
I ncl usi o n of S peci al P o p ul ati o ns
N ot a p plica ble.
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y s u bjects meet i n g all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria ma y be e nr olle d i nt o 
t he trial. Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical care, 
t he I nvesti gat or will e ns ure t hat t he s u bject has pr o vi de d writte n i nf orme d c o nse nt f oll o wi n g t he 
pr oce d ure descri be d i n Secti o n 9. 2.
F or s u bjects i n P hase Ia a n d I b, arc hi val t u m or material m ust be a vaila ble, eit her as a bl oc k or 
sli des ( m ost rece nt material) . If n o arc hi val material is a vaila ble t he n a fres h bi o ps y  sh o ul d be 
ta ke n.
All s u bjects i n t he a ncillar y c P o P part of t he trial m ust a gree t o ha ve t u m or bi o psies 
c ollecte d.
5. 3. 1
I ncl usi o n Criteri a
T o be eli gi ble t he s u bject m ust f ulfil l all of t he f oll o wi n g criteria:
1.
S u bjects m ust ha ve:
a. P h ase I a p art : a d va nce d s oli d t u m ors or metastases i ncl u di n g l ym p h o ma l ocalize d i n t he
hea d a n d nec k re gi o n or t h ora x wit h a n i n dicati o n f or fracti o nate d palliati ve R T ( Ar m A); 
or treat me nt-naï ve
S C C H N eli gi ble f or fracti o nate d c urati vel y i nte n de d R T wit h 
c o nc urre nt cis plati n ( Ar m B)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 4 9
b. P h ase I b p art : treat me nt-naï ve S ta ge III A/ B N S C L C n ot eli gi ble f or s ur gical resecti o n
or c o nc urre nt c he m ora diati o n ( Ar m A e x pa nsi o n c o h ort) or treat me nt-naï ve S C C H N 
eli gi ble f or fracti o nate d c urati vel y inte n de d R T wit h c o nc urre nt cis plati n ( Ar m B 
e x pa nsi o n c o h o rt)
c. A ncill ar y c P o P p art : a n y t u m or wit h at least 2 (s u b)c uta ne o us t u m or/ metastases at least 
2 c m a part w hic h are R T naï ve wit h a n i n dicati o n f or hi g h d ose palliati ve R T
2.
Meas ura ble or e val ua ble disease acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors 
(R E CI S T ) v 1. 1 (n ot re q uire d f or t he a ncillar y c P o P part of t he trial )
3.
Male or fe male s u bjects at least 1 8 y ears of a ge 
4.
Easter n C o o perati ve O nc ol o g y  Gr o u p p erf or ma nce stat us ( E C O G P S) ≤1
5.
M ust ha ve rea d, well u n derst o o d, a n d si g ne d a n d date d t he I nf or me d C o nse nt F or m (I C F); t he 
s u bject f ull y un dersta n ds t he re q uire me nts of t he trial a n d is willi n g t o c o m pl y wit h all trial 
visits a n d assess me nts
6.
A male partici pa nt m ust a gree t o use a n d t o ha ve t heir fe male part ners t o use a hi g hl y ef fecti ve 
c o ntrac e pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % per year) as detaile d i n 
A p pe n di x E of t his pr ot oc ol 1 4 d a y s bef ore first d ose of trial treat me nt, duri n g t he treat me nt 
peri o d a n d f or at least 9 0 da y s after t he last d ose of trial treat me nt a n d refrai n fr o m d o nati n g 
s per m d uri n g t his peri o d
7.
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt (see A p pe n di x E ), n ot 
breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies:
a. N ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P) as defi ne d i n  A p pe n di x E
O R
b. A W O C B P w h o a grees t o use a hi g hl y effecti ve c o ntrace pti o n (ie, met h o ds wit h a fail ure 
rate of less t ha n 1 % per year) , as detaile d i n A p pe n di x E of t his pr ot oc ol , 1 4 da y s bef ore 
t he start o f first d ose of trial treat me nt, d uri n g t he treat me nt peri o d a n d f or at least 9 0 d a y s
after t he last d ose of trial treat me nt
8.
L ife e x pecta nc y of ≥3 m o nt hs
( P hase Ia, Ar m A) or ≥6 m o nt hs
(P hase Ia, Ar m B a n d 
P hase I b).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 4 9
5. 3. 2
E xcl usi o n Criteri a
5. 3. 2. 1
P h ase I a/I b P arts
S u bjects are n ot eli gi ble f or t he P hase Ia or I b parts of t he trial if t he y fulfill a n y  of t he f oll o wi n g 
e xcl usi o n criteria:
1.
Pri or treat me nt c o nsisti n g of: 
a. C he m ot hera p y, i m m u n ot hera p y, h or m o nal t hera p y, bi ol o gic t hera p y, or a n y ot her 
a ntica ncer t hera p y or I M P wit hi n 2 8 da y s of first trial dr u g i nta ke ( 6 wee ks f or 
nitr os o ureas or mit o m y ci n C) f or P hase Ia, Ar m A s u bjects, a n d a n y pri or t hera p y for 
P hase I b s u bjects. F or s u bjects wi t h ra pi dl y gr o wi n g t u m ors l ocalize d i n t he hea d a n d 
nec k re gi o n or t h ora x w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 d a y s, i ncl usi o n ma y  
ta ke place if t here is n o resi d ual t o xicit y fr o m pre vi o us treat me nt ( ma xi m u m C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts [ C T C A E] G ra de 1)
b. Pri or R T t o t he sa me re gi o n wit hi n 1 2 m o nt hs
( P hase Ia, Ar m A ; s u bjects wit h t u m ors 
l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x ) or at a n y ti me pre vi o usl y (P hase Ia, Ar m 
B ; treat me nt-naï ve s u bjects wit h S C C H N a n d P hase I b; treat me nt-naï ve s u bjects wit h
S ta ge III A/ B N S C LC or S C C H N )
c. E xte nsi ve pri or R T o n ≥3 0 % of b o ne marr o w reser ve as j u d ge d b y  the In vesti gat or or 
pri or b o ne marr o w/ste m cell tra ns pla ntati o n wit hi n 5 years bef ore trial start
2.
Resi d ual t o xicit y  d ue t o pri or t hera py wit h n o ret ur n t o baseli ne or ≤Gra de 1 (e xce pt al o pecia 
acc or di n g t o C T C A E v 4. 0 3)
3.
S ur gical i nter ve nti o n , i ncl u di n g bi o psies a n d de ntal r o ot s ur geries, wit hi n 2 8 da y s pri or t o t he 
first d ose of I M P a d mi nistrati o n or ha vi n g partici pate d i n a n i nter ve nti o nal cli nical trial wit hi n 
2 8 da y s pri or t o t he first d ose of I M P a d mi nistrati o n f or P hase Ia/I b. Nee dle bi o psies are n ot 
c o nsi dere d as s ur ger y .
4.
P o or vital or ga n f u ncti o ns defi ne d as: 
a. B o ne marr o w 
i m pair me nt as e vi de nce d b y  he m o gl o bi n < 1 0. 0 g/ d L
( 5. 7 µ m ol/ L) , 
ne utr o p hil c o u nt < 1. 0 × 1 0 9/L , platelets < 1 0 0 × 1 0 9/ L
b. Re nal i m pair me nt as e vi de nce d b y ser u m creati ni ne > 1. 5 × u p per li mit of n or mal ( U L N )
c. Li ver f u ncti o n a b n or malit y as defi ne d b y  total bilir u bi n > 1. 5 × U L N or as partate 
a mi n otra nsferase (A S T )/ala nine a mi n otra nsferase ( A L T ) > 2. 5 × U L N
(e xce pt f or 
s u bjects wit h li ver i n v ol ve me nt, w h o ca n ha ve A S T/ A L T > 5 × U L N )
5.
Si g nifica nt car diac c o n d ucti o n a b n or malities,i ncl u di n g a hist or y  of l o n g Q Tc s yn dr o me a n d/ or 
pace ma ker, or i m paire d car di o vasc ular f u ncti o n s uc h as Ne w Y or k Heart Ass ociati o n 
classificati o n sc ore > 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 4 9
6.
H y perte nsi o n u nc o ntr olle d b y  me dicati o n 
7.
K n o w n C N S metastases u nless pre vi o usl y treate d b y  RT, sta ble b y  c o m p ute d t o m o gra p hy (C T )
sca n f or at least 3 m o nt h s wit h o ut e vi de nce of cere bral e de ma a n d n o re q uire me nt f or 
c ortic oster oi ds or a ntic o n v ulsa nts
8.
K n o w n h u ma n i m m u n o deficie nc y vir us (HI V) p ositi vit y , k n o w n cli nicall y si g nifica nt hist or y 
of he patitis (e. g., He patitis B [ H B V] or He patitis C [ H C V] vir us), c urrent alc o h ol a b use, or 
cirr h osis . Scree ni n g f or HI V t o be perf or me d acc or di n g t o l ocal practice a n d l ocal re g ulat or y 
g ui da nce. Testi n g f or HI V a n d H B V/ H C V s h o ul d be re peate d if t he s u bject teste d ne gati ve f or 
t he vir uses m ore t ha n 3 m o nt hs bef ore trial e nr oll me nt
9.
O n g oi n g acti ve i nfecti o n ot her t ha n HI V, H B V or H C V , or treat me nt wit h a li ve atte n uate d 
vacci ne wit hi n 3 0 da y s of d osi n g
1 0. Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat m a y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he I MP, c urre nt use of 
perc uta ne o us e n d osc o pic gastr ost o m y ( P E G) t u bes
1 1. Hist or y  of a n y ot her si g nifica nt me dical disease s uc h as maj or gastric or s mall b o wel s ur ger y, 
rece nt drai na ge of si g nifica nt v ol u mes (as per I n vesti gat or’s j u dge me nt) of ascites or ple ural 
eff usi o n or a ps yc hiatric c o n diti o n t hat mi g ht i m pair t he s u bject’s well -bei n g or precl u de f ull 
partici pati o n i n t he trial
1 2. K n o w n h y perse nsiti vit y  t o t he trial treat me nt or t o o ne or m ore of t he e xci pie nts use d
1 3. Pre g na n c y or lactati o n peri o d
1 4. Le gal i nca p acit y or li mite d le gal ca pacit y
1 5. S u bjects c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of C Y P 3 A or C Y P 2 C 1 9 
m ust st o p at least 1 wee k pri or t o ta ki n g M 3 8 1 4 . S u bjects recei vi n g p ote nt i n d ucers of C Y P 3 A 
or C Y P 2 C 1 9 m ust st o p at least 3 wee ks pri or t o ta ki n g M 3 8 1 4 . T h ose recei vi n g dr u gs mai nly 
meta b olize d b y  CY P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y  the I nvesti gat or (a n d 
after o pti o nal c o ns ultati o n wit h t he S p o ns or) m ust st o p at least o ne da y pri or t o ta ki n g M 3 8 1 4 .
1 6. S u bjects c urre ntl y recei vi n g H2-bl oc ker or pr ot o n p u m p i n hi bit ors ( P PI s) ( or u na ble t o st o p at 
least 5 da ys pri or t o t he first treat me nt).
1 7. If t he pla n ne d ra diati o n fiel d i ncl u des a ny p art of t he es o p ha g us a n d t he s u bject has s ym pt o ms 
of o n g oi n g es o p ha gitis, t he s u bject is n ot eli gi ble, u nless a n es o p ha geal e n d osc o p y rules o ut 
t he prese nce of es o p ha gitis.
1 8. S u bject s w here m ore t ha n 1 0 % of t he t otal es o p ha g us v ol u me recei ves m ore t ha n 5 0 % of t he 
prescri be d R T d ose .
O ut of ra n ge la b orat or y  val ues ma y be reteste d wit hi n t he ti mefra me of t he scree ni n g peri o d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 4 9
5. 3. 2. 2
A ncill ar y Cli nic al Pr o of -of -Pri nci ple P art
S u bjects are n ot eli gi ble f or t he a ncillar y c P o P part of t he trial if t he y fulfill a n y of t he f oll o wi n g 
e xcl usi o n criteria:
1. Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n or ot her c hr o nic gastr oi ntesti nal disease or 
c o n diti o ns t hat ma y ha m per c o m plia nce a n d/ or a bs or pti o n of t he I M P
2. Hist or y  of a n y ot her si g nifica nt me dical disease s uc h as maj or gastric or s mall b o wel s ur gery, 
rece nt drai na ge of si g nifica nt v ol u mes of ascites or ple ural eff usi o n (as per I n vesti gat or’s 
j u d ge me nt) or a ps yc hiatric c o n diti o n t hat mi g ht i m pair the s u bject’s well -bei n g or precl u de 
f ull partici pati o n i n t he trial
3. K n o w n h y perse nsiti vit y  t o t he trial treat me nt or t o o ne or m ore of t he e xci pie nts use d 
4. Pre g na n c y or lactati o n peri o d
5. Le gal i nca pacit y or li mite d le gal ca pacit y
6. S u bjects c urre ntl y recei vi ng ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose of trial
dr u g) me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors of C Y P 3 A or C Y P 2 C 1 9 
m ust st o p at least 1 wee k pri or t o ta ki n g M 3 8 1 4 . S u bjects recei vi n g p ote nt i n d ucers of C Y P 3 A 
or C Y P 2 C 1 9 m ust st o p at least 3 wee ks pri or t o ta ki n g M 3 8 1 4 . T h ose recei vi n g dr u gs mai nl y 
meta b olize d b y  CY P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y  the I nvesti gat or (a n d after 
o pti o nal c o ns ultati o n wit h t he S p o ns or) m ust st o p at least o ne da y  pri or t o ta ki n g M 3 8 1 4 .
5. 4
Criteri a f or I niti ati o n of Tri al Tre at me nt
T his is a n o pe n la bel trial wit h o ut ra n d o mizati o n. S u bjects w h o pr o vi de writte n i nf or me d c o nse nt 
a n d w h o meet all rele va nt eli gi ble criteria will recei ve o pe n la bel M 3 8 1 4
at t he c urre ntl y r ecr uiti n g
c o h ort d ose le vel.
5. 5
Criteri a f or S u bject Wit h dr a w al
5. 5. 1
Wit h dr a w al fr o m Tri al T her a p y
T he s u bject m ust be wit h dra w n fr o m I M P i n t he e ve nt of a ny of t he f oll o wi n g:

Occ urre nce of a n e xcl usi o n criteri o n w hic h is cli nicall y rele va nt a n d affects t he s u bject’s safety,  
if disc o nti n uati o n is c o nsi dere d necessar y by t he I n vesti gat or a n d/ or S p o ns or pri or t o treat me nt 
c o m pleti o n 

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal dr u g (if a p plica ble)

Disc o nti n uati o n of R T

A d verse dr u g reacti o ns ( AD R s) t hat ca use R T dela y s of > 7 da y s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 4 9

Occ urre nce of A Es, if disc o nti n uati o n of trial dr u g is desire d or c o nsi dere d necessar y  by t he 
I n vesti gat or a n d/ or t he s u bject (if a p plica ble)

Occ urre nce of pre g na nc y

Use of a n o n per mitte d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 6,  w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he I M P

Ne w sta n dar d e xisti n g t hera py t hat is c o nsi dere d m ore s uita ble acc or di n g t o t he Pri nci pal 
I n vesti gat or

N o nc o m plia nce t hat is dee me d b y t he I n vesti gat or or t he S p o ns or t o c o m pr o mise s u bject safet y 
or trial i nte grit y .
5. 5. 2
Wit h dr a w al fr o m t he Tri al
S u bjects are free t o disc o nti n ue t he trial at a n y ti me wit h o ut gi vi n g t heir reas o ns. 
A s u bject m ust be wit h dra w n i n t he e ve nt of a ny of t he f oll o wi n g:

Wit h dra wal of t he s u bject’s c o nse nt

Partici pati o n i n a n y ot her trial d uri n g t he d urati o n of t his trial ( u p t o 1 2 m o nt hs i n P hase Ia a n d 
I b parts a n d u p t o 3 2 da ys i n t he a ncillar y c P o P part)

Pre g na nc y pri or t o treat me nt c o m pleti o n or u p t o 3 0 da y s after R T.
If a s u bject has faile d t o atte n d sc he d ule d trial assess me nts, t he I n vesti gat or m ust deter mi ne t he 
reas o ns a n d t he circ u msta nces as c o m pletely a n d acc uratel y as p ossi ble.
I n case of pre mat ure wit h dra wal fr o m t he trial, assess me nts f or Fracti o n Da y  1 0 (Ar m A) or last 
Fracti o n D a y ( 3 3 t o 3 5; Ar m B) i n P hase Ia , Fracti o n Da y  3 3 (N S C L C c o h ort ) or last Fracti o n Da y 
( 3 3 t o 3 5; S C C H N c o h ort) i n P hase I b a n d t he E O T visit s h o ul d be perf or me d , if p ossi ble wit h 
f oc us o n t he m ost rele va nt assess me nts (Ta ble 1 [ P hase Ia – Ar m A
ca ps ule c o h orts ], Ta ble 2
[ P hase Ia – Ar m A ta blet c o h orts], Ta ble 3 [first 3 s u bjects i n P hase Ib – Ar m A, N S C L C c o h ort], 
Ta ble 4 [P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia: – Ar m B, S C C H N c o h ort], Ta ble 6
[ P hase I b – Ar m B, S C C H N c o h ort], a n d Ta ble 7 [a ncillar y c P o P part of t he trial]). I n an y  case, 
t he ap pr o priate electr o nic Case Re p ort F or m (e C R F) secti o n m ust be c o m plete d.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he cli nical trial ma y  be ter mi nate d pre mat urel y at t he re q uest of Healt h A ut h orities or if ne w 
safety or efficac y i nf or mati o n lea ds t o a n u nfa v ora b le be nefit-ris k j u d g me nt (e. g., d ue t o e vi de nce 
of i na de q uate dr u g e x p os ure; occ urre nce of si g nifica nt pre vi o usl y  un k n o w n a d verse reacti o ns or 
u ne x pecte dl y  hi gh i nte nsit y  or i nci de nce of k n o w n a d verse reacti o ns; or o t her u nfa v ora ble safety 
fi n di n gs i n t his trial or t he FI M trial or a ny ot her trial ).
T he S p o ns or m a y  disc o nti n ue t he trial if it bec o mes u nj ustifia ble f or me dical or et hical reas o ns, 
f or p o or e nr oll me nt ma ki n g c o m pleti o n of t he trial wit hi n a n acce pta ble ti me fra me u nli kel y, or 
beca use of di sc o nti n uati o n of cli nical de vel o p me nt of M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 4 9
Healt h A ut h orities a n d I nde pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs) 
will be i nf or me d a b o ut t he disc o nti n uati o n of t he trial i n acc or da nce wit h a p plica ble re g ulati o ns.
5. 7
Defi niti o n of E n d of Tri al
T he trial will e n d after t he last s u bject i n t he P hase I b part has c o m plete d t he 1 -ye ar f oll o w-u p 
peri o d or all s u bjects i n t he a ncillar y c P o P part of t he trial ha ve c o m plete d t he 3 0- da y  foll o w u p ,
w hic he ver c o mes later.
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he Tri al
T he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o a n acti ve s u bsta nce or a place b o bei n g 
teste d or use d as a refere nce t hera py i n a cli nical trial, i ncl u di n g pr o d ucts t hat ha ve a mar keti n g 
a ut h orizati o n b ut are f or m ulate d , pac ka ge d , or a d mi nistere d differe ntl y  fr o m t he a ut h orize d f or m, 
use d f or a n u na ut h orize d i n dicati o n, or use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.  
I n t his trial, t he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o t he i n vesti gati o nal dr u g M 3 8 1 4 , 
w hic h is t he o nl y  IM P use d i n t his trial.
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
M S C 2 4 9 0 4 8 4 A, I nter nati o nal U ni o n of P ure a n d A p plie d C he mistr y  na me ( S)-[ 2-chl or o - 4-fl u or o-
5- ( 7-m or p h oli n -4 -yl -q ui naz oli n - 4-yl )-p he n y l]-( 6-met h o x y -p y ri dazi n- 3-yl )-met ha n ol, is s u p plie d 
as 1 0 m g (size 4, i v or y ), 5 0 m g (size 0, i v or y ), a n d 1 0 0 m g (size 0, S we dis h ora n ge) har d gelati n 
ca ps ules, as well as 5 0 m g ( bei ge t o yell o w ca plet) fil m-c oate d ta blets f or oral a d mi nistrati o n. 
Ca ps ules c o nsist of b ul k dr u g s u bsta nce fille d i nt o har d gelati n ca ps ules of differe nt size a n d/ or 
c ol or, de pe n di n g o n t he d ose stre n gt h. N o f urt her e xci pie nts are use d. Har d gelati n ca ps ule s hells 
meet t he s u p plier’s ( Ca ps u gel ®) sta n dar ds a n d gelati n is of p har mac o p oeial gra de .
Fil m -c oate d ta blets c o nsist of a ta blet c ore c o m p ose d of e xtr u date ( 2 0 % ( w/ w) dr u g s u bsta nce/ 8 0 % 
( w/ w) c o p o vi d o ne s oli d dis persi o n) a n d ot her e xci pie nts 
 
. All e xci pie nts use d i n t he ta blet f or m ulati o n 
are of c o m pe n dial gra de. S u p plier’s certificates s h o w t hat t here is n o tra ns missi ble s p o n gif or m 
e nce p hal o pat h y ris k.
M S C 2 4 9 0 4 8 4 ca ps ules a n d ta blets are pr o vi de d i n 
 a n d s h o ul d be 
st ore d
. T he ta blets s h o ul d n ot be fr oze n.
6. 2
Descri pti o n of C o nc urre nt C he m ot her a p y
C he m o t hera py will be a d mi nistere d i n c o m bi nati o n wit h t he I M P ( M 3 8 1 4 ) i n s u bjects e nr olle d i n 
Ar m B. T he c he m ot hera p y a ge nt is cis plati n w hic h is c o nsi dere d S o C f or t his i n dicati o n. T his 
c he m ot hera pe utic a ge nt is a d mi nistere d via i ntra ve n o us (i v) i nf usi o n. D ose a n d d ose re gi me n of 
cis plati n is t o be a p plie d i n li ne wit h c urre nt me dical g ui deli nes ( Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k , A merica n C olle ge of C hest P h y sicia ns/ A S C O, a n d E ur o pea n S ociet y  for Me dical 
O nc ol o g y ) wit h refere nce t o t he S o C f or c o nc urre nt C R T wit h cis plati n i n t he treat me nt of s u bjects 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 4 9
wit h S C C H N. T w o cis plati n d osi n g sc he d ules are all o we d, 1 0 0 m g/ m 2 gi ve n t wice or 4 0 m g / m2
gi ve n wee kl y d uri n g t he R T treat me nt . I n ad diti o n t o me dical g ui deli nes, d osi n g of cis plati n is t o 
be 
perf or me d 
i n acc or da nce wit h 
t he pr o d uct 
la beli n g a n d cli nical site’s s pecific 
p olicies /i nstr ucti o ns. Cis plati n
will n ot be s u p plie d b y  the S p o ns or. It will be use d fr o m 
c o m merciall y a vaila ble s o urces a n d pre pare d i n acc or da nce wit h its pr o d uct la beli n g.
6. 3
D os a ge a n d A d mi nistr ati o n
6. 3. 1
P h ase I a a n d I b P arts
S u bjects wit h l ocall y ad va nce d disease , as descri be d i n t he Eli g i bilit y Criteria ( Secti o n 5. 3 ), will 
be assi g ne d t o recei ve M 3 8 1 4
at a starti n g d ose of 1 0 0 m g Q D ( Ar m A) or 5 0 m g Q D ( Ar m B)
w hic h will be gi ve n 1. 5 h o urs ( ± 3 0 mi n utes) bef ore eac h R T fracti o n f or u p t o 1 0 fracti o ns
( Ar m A) or f or 3 3 t o 3 5 fracti o ns ( Ar m B) .
I n t he P hase Ia part of t he trial a n d f or t he first 3 s u bjects i n P hase I b ( N S C L C e x pa nsi o n c o h ort) , 
t he d ose of M 3 8 1 4
will
be i ncrease d acc ordi n g t o t he d ose escalati o n r ules descri be d i n
Secti o n 5. 1. 1. N o i ntras u bject d ose escalati o n is per mitte d.
S u bjects will ta ke t heir assi g ne d d ose of M 3 8 1 4
Q D wit h a f ull glass of water (a p pr o xi matel y 
2 4 0 m L / 8 fl ui d o u nces). 
S u bjects will be i nstr ucte d as f oll o ws:

O n d a y s wit h serial P K c ollecti o ns (Fracti o n Da y s 1 a n d 1 0 ), t o fast 1. 5 h o urs pri or t o d ose 
a d mi nistrati o n a n d c o nti n ue t o fast f or 4 h o urs p ost d os e

O n all ot her Fracti o n Da y s, t o fast 1. 5 h o urs pri or t o d ose a d mi nistrati o n a n d c o nti n ue t o fast 
f or 1 h o ur p ost d os e

Ta ke t he prescri be d d ose of M 3 8 1 4
1 . 5 h o urs ( ± 3 0 mi n utes) bef ore R T is starte d

S wall o w t he ca ps ules or ta blets w h ole a n d n ot bite i nt o t he ca ps ules, brea k or o pe n t he m, or 
atte m pt t o diss ol ve t he c o nte nts i n w ater pri or t o ta ki n g t heir assi g ne d d ose

T he d oses o n Fracti o n Da y s 1, 2, 6 a n d 1 0 s h o ul d n ot be ta ke n u ntil t he pre d ose P K c ollecti o n 
has bee n c o m plete d.
If a s u bject v o mits after ta ki n g t heir d ose of M 3 8 1 4 , t he y sh o ul d be gi ve n a n a ntie metic b ut n o 
f urt her d ose wi ll be gi ve n t hat da y . Pr o p h y lactic a ntie metics s h o ul d t he n be gi ve n pri or t o 
s u bse q ue nt d oses of M 3 8 1 4 . An y  cha n ge fr o m d osi n g sc he d ule, d ose i nterr u pti o ns, or d ose 
re d ucti o ns s h o ul d be rec or de d i n t he e C R F.
T he f or mal criteria f or M 3 8 1 4 , R T , a n d cis plati n d ose m o dificati o n i n t he trial are i ncl u de d i n 
Ta ble 1 3.
I n ge neral, eac h s u bject will sta y on t he M 3 8 1 4 , R T a n d cis plati n (as a p plica ble) d ose le vel 
assi g ne d i n t he trial u nless treat me nt nee ds t o be i nterr u pte d, m o difie d or st o p pe d. I n all ot her 
sit uati o ns, if t he In vesti gat or belie ves t hat a treat me nt-e mer ge nt a d verse e ve nt (T E A E ) is d ue t o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6- 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 4 9
cis plati n, t he d ose is t o be m o difie d acc or di n g t o t he pac ka ge i nsert / S m P C or l ocal g ui deli nes. A 
cis plati n d ose dela y  of u p t o 1 wee k is per mitte d, i n a d diti o n t o t he s pecific g ui da nce pr o vi de d 
bel o w.
M 3 8 1 4 will be pr o vi de d as ta blet f or m ulati o n of 5 0 m g f or oral a d mi nistrati o n. D osi n g sc he d ule 
of t he ta blet f or m ulati o n f oll o ws t he descri pti o n gi ve n f or t he ca ps ule f or m ulati o n a b o ve. T he 
ta blet f or m ulati o n will be i nitiall y assesse d i n P hase Ia Ar m A ta ki n g i nt o acc o u nt t he a vaila ble 
safety, t olera bilit y a n d P K res ults fr o m t he ca ps ule. Sta n dar d 3 + 3 d ose escalati o n desi g n criteria 
will a p pl y. C o m paris o n of si n gle d ose P K data bet wee n t he ta blet a n d t he ca ps ule will g ui de t o 
defi ne t he ta blet d oses i n P hase Ia Ar m B a n d i n t he P hase I b parts.
F or s u bjects in Ar m B recei vi n g cis plati n:

T here will be n o d ose escalati o n of cis plati n a b o ve t he pr ot oc ol -s pecifie d d ose . H o we ver ,
cis plati n d ose re-escalati o n after a n i nitial d ose re d ucti o n, f oll o wi n g t he ma n ufact urer’s la bel, 
is per mitte d.

D ose m o dificati o ns f or t o xicit y sh o ul d be i n de pe n de ntl y assesse d pri or t o d ose a d mi nistrati o n 
at eac h visit f oll o wi n g i nstit uti o nal g ui deli nes or Ta ble 1 3 i n t he a bse nce of s uc h g ui deli nes.

Pr o p h y lactic gra n ul oc y t e-c ol o n y sti m ulati n g fact or ( G-C S F )
m a y  be i m ple me nte d if 
ne utr o pe nia res ults i n d ose re d ucti o n or d ose dela y  at pri or d oses, as s u g geste d i n t he A S C O
g ui deli nes. T hera pe utic use of he mat o p oiet ic c ol o n y-sti m ulati n g fact ors is per mitte d f oll o wi n g 
A S C O g ui deli nes.

I n t he e ve nt a s u bject e x perie nces ne utr o pe nia ,a n d G- C S F is i nitiate d,a n d ne utr o pe nia rec o vers 
wit hi n 4 8 h o urs after be gi n ni n g treat me nt wit h G- C S F, G- C S F m a y  be i m ple me nte d i n t he 
ma na ge me nt of ne utr o pe nia i n t his s u bject t o a v oi d d ose re d ucti o ns or h ol di n g a d ose.
He m o gl o bi n m ust be ≥1 0 g/ d L at F D 1 a n d m ust be ≥9 g/ d L f or all s u bse q ue nt d oses. If 
he m o gl o bi n is <9 g/ d L t he n a p pr o priate meas ures acc or di n g t o sta n dar d cli nical practice m ust be 
ta ke n pri or t o a ny f urt her d ose a d mi nistrati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 4 9
T a ble 1 3
D ose M o dific ati o ns f or M 3 8 1 4 , R a di ot her a p y, a n d Cis pl ati n D uri n g t he Tri al
T o xi cit y
D o s e M o difi c ati o n s
M 3 8 1 4
a
R a di ot h er a p y b
Ci s pl ati n
( o nl y f or Ar m B a n d i n t h e a b s e n c e 
of i n stit uti o n al g ui d a n c e o n 
ci s pl ati n d o s e m o difi c ati o n s)
T o xi citi e s i n R a di ati o n Fi el d Gr a d e 4

M u c o siti s
( mu c o s al i nfl a m m ati o n)

R a di ati o n d er m atiti s
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt o n c e s e v erit y 
r e s ol v e s t o Gr a d e ≤3.
T e m p or aril y i nt err u pt 
tr e at m e nt. R e s u m e tr e at m e nt 
o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤3.
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt o n c e s e v erit y 
r e s ol v e s t o Gr a d e ≤3.
S y st e mi c T o xi citi e s

F e bril e n e utr o p e ni a

Gr a d e 3 t hr o m b o c yt o p e ni a wit h m e di c all y c o n c er ni n g bl e e di n g

H e m at ol o gi c T o xi citi e s: A n y Gr a d e ≥4 t o xi cit y, e x cl u di n g:

Gr a d e 4 n e utr o p e ni a l a sti n g f or ≤5 d a y s a n d n ot 
a s s o ci at e d wit h f e v er

I s ol at e d Gr a d e 4 l y m p h o c yto p e ni a wit h o ut cli ni c al c orr el at e
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e . I n c a s e of 
a s e c o n d r e c urr e n c e at t h e s a m e 
gr a d e , p er m a n e ntl y di s c o nti n u e 
I M P.
N o a cti o n t o b e t a k e n .
F e bril e n e utr o p e ni a a n d Gr a d e 3 
t hr o m b o c yt o p e ni a wit h bl e e di n g: 
p er m a n e nt 2 5 % d o s e r e d u cti o n.
If o n t h e d a y of s c h e d ul e d tr e at m e nt 
wit h ci s pl ati n A N C i s < 1 5 0 0/ m m 3 , 
h ol d tr e at m e nt u ntil A N C 
≥1 5 0 0/ m m 3 , t h e n tr e at at 1 0 0 % 
d o s e.
If o n t h e d a y of s c h e d ul e d tre at m e nt 
wit h ci s pl ati n t h e pl at el et c o u nt i s 
< 7 5, 0 0 0/ m m 3 , h ol d tr e at m e nt u ntil 
pl at el et s ar e > 7 5, 0 0 0/ m m 3, t h e n tr e at 
at 1 0 0 % d o s e.
S y st e mi c T o xi citi e s

N o n h e m at ol o gi c T o xi citi e s

A n y Gr a d e ≥3 t o xi cit y, e x cl u di n g:

Di arr h e a of Gr a d e ≥3 ( ≤3 d a y s d ur ati o n) f oll o wi n g 
a d e q u at e a n d o pti m al t h er a p y

N a u s e a a n d v o miti n g of Gr a d e ≥3 ( ≤3 d a y s d ur ati o n) 
wit h a d e q u at e a n d o pti m al t h er a p y

F ati g u e or h e a d a c h e of Gr a d e 3 ( ≤7 d a y s d ur ati o n) 
f oll o wi n g i niti ati o n of a d e q u at e s u p p orti v e c ar e

A n y ot h er si n gl e l a b or at or y v al u e s of Gr a d e ≥3 o ut of 
t h e n or m al r a n g e t h at h a v e n o cli ni c al si g nifi c a n c e, a n d 
t h at r e s ol v e t o Gr a d e ≤2 wit h a d e q u at e m e a s ur e s 
wit hi n 7 d a y s
T e m p or aril y i nt err u pt tr e at m e nt .
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e . I n c a s e of 
a s e c o n d r e c urr e n c e at t h e s a m e 
gr a d e , p er m a n e ntl y di s c o nti n u e 
I M P.
I n c a s e of Gr a d e ≥3 li v er e n z y m e 
v al u e s, t h e s u bj e ct m u s t b e 
m o nit or e d at l e a st e v er y 4 d a y s 
u ntil r e c o v er y t o Gr a d e ≤2.
N o a cti o n t o b e t a k e n .
I n stit uti o n al g ui d eli n e s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 4 9

E vi d e n c e of st u d y tr e at m e nt -r el at e d h e p at o c ell ul ar i nj ur y 
f or m or e t h a n 3 d a y s, s u c h a s > 5- f ol d el e v ati o n s a b o v e 
t h e U L N of A L T or A S T ( C T C A E Gr a d e 3 or 4) wit h or 
wit h o ut el e v ati o n of s er u m t ot al bilir u bi n t o > 2 × U L N, 
wit h o ut i niti al fi n di n g s of c h ol e st a si s ( el e v at e d s er u m 
a k ali n e p h o s p h at a s e) or ot h er a p p ar e nt cli ni c al c a u s alit y.
A E = a d v er s e e v e nt; A L T = al a ni n e a mi n otr a n sf er a s e; A N C = a b s ol ut e n e utr o p hil c o u nt; A S T = a s p art at e a mi n otr a n sf er a s e; C T C A E = c o m m o n t er mi n ol o g y crit eri a f or a d v er s e e v e nt s; 
I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; R T = r a di ot h er a p y; U L N = u p p er li mit of n or m al .
N ot e: S e v erit y of A E s will b e gr a d e d u si n g t h e C T C A E ( v 4. 0 3) t o xi cit y gr a d e s.
a A s all tr e at m e nt s wit h M 3 8 1 4
wi ll b e gi v e n i n c o m bi n ati o n wit h R T, a n i nt err u pti o n i n t h e a d mi ni str ati o n of R T w o ul d l e a d t o a n i nt err u pti o n i n tr e at m e nt wit h M 3 8 1 4 .
b A m a xi m u m R T d el a y of u p t o a n d i n cl u di n g 7 d a y s i n t ot al i s all o w e d wit hi n t h e c o m pl et e tr e at m e nt p eri o d. If R T a n d M 3 8 1 4
tr e at m e nt h a v e t o b e d el a y e d b y m or e t h a n 7 d a y s, t h e 
s u bj e ct m u st b e di s c o nti n u e d fr o m M 3 8 1 4 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 4 9
A s all treat me nts wit h M 3 8 1 4
will be gi ve n i n c om bi nati o n wit h R T , a n i nterr u pti o n i n t he 
a d mi nistrati o n of R T w o ul d lea d t o a n i nterr u pti o n i n treat me nt wit h I M P. See Secti o n 6. 6. 3. 1 f or 
details o n ha n dli n g R T treat me nt dela y s.
6. 3. 1. 1
D os a ge a n d A d mi nistr ati o n of C o nc urre nt Cis pl ati n
T he c urre ntl y pr o p ose d re gi me n f or treat me nt-naï ve s u bjects wit h S C C H N i n P hase Ia ( Ar m B) 
a n d P hase I b ( S C C H N e x pa nsi o n c o h ort) c o nsists of Q D a d mi nistrati o n of M 3 8 1 4
o n eac h R T 
fracti o n da y t o get her wit h t he S o C (cis plati n).
O n Fracti o n D a y s 1 a n d 3 1 f or t he 1 0 0 m g/ m 2 d ose , or wee kl y  for t he 4 0 m g/ m 2 d ose , cis plati n 
will be gi ve n acc or di n g t o i nstit uti o nal g ui deli nes.
T he ti mi n g of ra di ot hera p y after t he a d mi nistrati o n of cis plati n will als o f oll o w i nstit uti o nal 
g ui deli nes, a p plica ble f or P hase Ia, A r m B ( d ose escalati o n) a n d t he Ar m B ( S C C H N) e x pa nsi o n
c o h ort o nl y . A d mi nistrati o n of M 3 8 1 4
will ta ke place 1. 5 h o urs ( ± 3 0 mi n utes) bef ore t he start of 
ra di ot hera py (see Secti o n 6. 3. 1) .
B o d y s urface area (B S A) s h o ul d be calc ulate d base d o n a sta n dar d f or m ula , s uc h as t he M osteller 
f or m ula [9 ]:
B S A ( m²) = ([ Hei g ht (c m) × Wei g ht( k g) ]/ 3 6 0 0)½
e. g. B S A = s q uare r o ot([c m × k g] / 3 6 0 0)
or, i n i nc hes a n d p o u n ds:
B S A ( m²) = ([ Hei g ht(i n) × Wei g ht(l bs)]/ 3 1 3 1 )½
If t here is a c ha n ge i n b o d y  wei g ht of at least 1 0 perce nt, t he i n di vi d ual cis plati n d ose s h o ul d be 
recalc ulate d. Ot her wise, t he i nitial B S A s h o ul d be utilize d f or s u bse q ue nt d oses.
6. 3. 1. 1. 1
Pre d osi n g C o nsi der ati o ns f or Cis pl ati n
Cis plati n is a d mi nistere d t o S C C H N s u bjects as part of t he trial. As wit h m ost c yt ot o xic re gi me ns, 
t his dr u g is prece de d a n d acc o m pa nie d b y  su p p orti ve care. Ge neral g ui da nce o n t he use of cis plati n 
is pr o vi de d. H o we ver, In vesti gat or s are referre d t o a n d nee d t o f oll o w t he pac ka ge i nsert, t he 
s u m mar y of pr o d uct c haracteristics ( S m P C), a n d t heir l ocal p olicies /i nstr ucti o ns f or t he 
a d mi nistrati o n of cis plati n.
Mai n pre d osi n g meas ures f or cis plati n are pr o vi de d i n  Ta ble 1 4 bel o w a n d nee d t o be assesse d f or 
t he i n di vi d ual s u bject pri or t o t he first, b ut als o f or s u bse q ue nt a d mi nistrati o ns of cis plati n. N ote 
t hat s o me meas ures ma y be gi n se veral da ys bef ore act ual treat me nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 4 9
T a ble 1 4
Pre d osi n g C o nsi der ati o ns f or Cis pl ati n
I s s u e/I n di c ati o n
R e c o m m e n d e d St e p s
Pr e- e m e si s
F oll o w c urr e nt M A S C C/ E S M O a or N C C N b g ui d eli n e s f or c h e m ot h er a p y -i n d u c e d 
n a u s e a a n d v o miti n g f or a “ hi g h ri s k” r e gi m e n
H y dr ati o n/
n e p hr ot o xi cit y
P er p a c k a g e i n s ert/S m P C f or ci s pl ati n c. Ci s pl ati n c a u s e s s e v er e c u m ul ati v e 
n e p hr ot o xi cit y. A uri n e o ut p ut of 1 0 0 m L/ h o ur or gr e at er will t e n d t o mi ni mi z e 
ci s pl ati n n e p hr ot o xi cit y. A d e q u at e h y dr ati o n m u st t h er ef or e b e m ai nt ai n e d t o 
c a u s e s uffi ci e nt di ur e si s pri or t o, d uri n g a n d aft er tr e at m e nt wit h ci s pl ati n. N e xt 
t o i v i nf u si o n, f or c e d di ur e si s m a y b e r e q uir e d a n d m or e o v er s u bj e ct s ar e t o b e 
r e q u e st e d t o dri n k a p pr o pri at e q u a ntiti e s of li q ui d s f or 2 4 h o ur s aft er ci s pl ati n 
i nf u si o n t o e n s ur e a d e q u at e uri n e s e cr eti o n.
M y el o s u p pr e s si o n/
n e utr o p e ni a
R ef er t o t h e c urr e nt p a c k a g e i n s ert/ S m P C a n d l o c al g ui d a n c e f or m o difi c ati o n s 
i n d o s e a n d s c h e d ul e of ci s pl ati nc. Ci s pl ati n d o s e s h o ul d b e wit h h el d if pl at el et 
c o u nt i s l e s s t h a n 7 5, 0 0 0 c ell s/ m m 3 or n e utr o p hil c o u nt i s l e s s t h a n 
1 5 0 0 c ell s/ m m 3 .
Pri m ar y pr o p h yl a xi s wit h G - C S F i n or d er t o r e d u c e t h e ri s k of f e bril e n e utr o p e ni a 
( F N) i s n ot r e c o m m e n d e d, a c c or di n g t o A S C Od a n d E S M O g ui d eli n e s. F N i s 
d efi n e d a s or al t e m p er at ur e > 3 8. 5° C or t w o c o n s e c uti v e r e a di n g s of > 3 8° C f or 
2 h o ur s a n d a n a b s ol ut e n e utr o p hil c o u nt < 0. 5 × 1 0 9 / L, or e x p e ct e d t o f all b el o w 
0. 5 × 1 0 9 / L. S e c o n d ar y pr o p h yl a xi s wit h C S F s i s r e c o m m e n d e d f or s u bj e c t s w h o 
e x p eri e n c e d a n e utr o p e ni c c o m pli c ati o n fr o m a pr e vi o u s c y cl e of c h e m ot h er a p y 
(f or w hi c h pri m ar y pr o p h yl a xi s w a s n ot r e c ei v e d), i n w hi c h a r e d u c e d d o s e or 
tr e at m ent d el a y m a y c o m pr o mi s e di s e a s e-fr e e or O S or tr e at m e nt o ut c o m e . T h e 
s e c o n d ar y pr o p h yl a xi s s h o ul d f oll o w A S C O or E S M O or l o c al g ui d eli n e s.
T h e d o s a g e i n str u cti o n s s h o ul d f oll o w t h e l o c al g ui d eli n e s or t h e A S C O or 
E S M O g ui d eli n e s.
Ot ot o xi cit y/
n e ur ot o xi cit y
P er p a c k a g e i n s ert/ S m P C f or ci s pl ati n c. Ci s pl ati n i s pr o v e n t o b e c u m ul ati v e 
ot ot o xi c a n d n e ur ot o xi c. N e ur ol o gi c e x a mi n ati o n a n d m o nit ori n g of p ot e nti al 
ot ot o xi cit y i s t o b e p erf or m e d pri or t o e a c h ci s pl ati n d o si n g a n d d uri n g t h e 
tr e at m e nt.
A S C O = A m eri c a n S o ci et y of Cli ni c al O n c ol o g y ; C S F = c ol o n y sti m ul ati n g f a ct or ; E S M O = E ur o p e a n S o ci et y f or 
M e di c al O n c ol o g y ; F N = f e bril e ne utr o p e ni a; G -C S F = g r a n ul o c yt e-c ol o n y sti m ul ati n g f a ct or ; i v = i ntr a v e n o u s;
M A S C C = M ulti n ati o n al A s s o ci ati o n of S u p p orti v e C ar e i n C a n c er ; N C C N = N ati o n al C o m pr e h e n si v e C a n c er 
N et w or k ; S m P C = s u m m ar y of pr o d u ct c h ar a ct eri sti c s; O S = o v er all s ur vi v al.
a A n n al s of O n c ol o g y 2 1 ( S u p pl e m e nt 5): v 2 3 2 – v 2 4 3, 2 0 1 0
b N C C N G ui d eli n e s A nti e m e si s v er si o n 2/ 2 0 1 6
c htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ m e di ci n e/ 2 5 9 4 4 ( L a st U p d at e d o n e M C 0 9 J a n u ar y 2 0 1 5 )
d J Cli n O n c ol 3 3: 3 1 9 9 -3 2 1 2
6. 3. 1. 2
R a di ot her a p y
A n o ver vie w of t he R T tec h ni q ue ( inte nsit y- m o d ulate d ra di o t hera p y [IM R T] ) f or d os e escalati o n 
Ar m B ( S C C H N) i n P hase Ia a n d b ot h e x pa nsi o n c o h orts i n P hase I b is gi ve n i n A p pe n di x D .
6. 3. 2
A ncill ar y c P o P P art
S u bjects will recei ve a si n gle hi g h d ose of R T ( 1 0-2 5 G y ) gi ve n o n Lesi o n 1 o n Da y 1 . O n Da y 2, 
s u bjects will recei ve a si n gle d ose of M 3 8 1 4
i n c o m bi nati o n wit h
a si n gle hi g h d ose of R T 
( 1 0- 2 5 G y ) gi ve n o n Lesi o n 2. S u bject s will fast f or 1. 5 h o urs pri or t o d ose a d mi nistrati o n a n d 
c o nti n ue t o fast f or 1 h o ur p ost d os e. M 3 8 1 4
will be a d mi nistere d 1 . 5 h o ur ( ± 3 0 mi n utes) bef ore
t he start of R T. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 4 9
T he d ose of M 3 8 1 4
t o be a d mi nistere d t o s u bjects i n s uccessi ve c o h orts of t he a ncillar y c P o P part 
of t he trial is s h o w n i n Ta ble 1 2.
6. 4
Assi g n me nt t o Tre at me nt Gr o u ps
All eli gi ble s u bjects will be assi g ne d t o recei ve o pe n la bel M 3 8 1 4 . S u bjects will be assi g ne d t o 
treat me nt se q ue ntially. D uri n g d ose escalati o n ( P hase Ia) a n d f or t he first 3 N S C L C s u bjects i n t he 
Ar m A e x pa nsi o n c o h ort ( P hase I b) , t he ne xt d ose le vel will be o pe n f or e nr oll me nt o nl y after t he 
D L Ts i n t he c urre nt d ose le vel ha ve bee n f ully e val uate d b y t he S M C a n d a f or mal S M C decisi o n 
t o pr ocee d t o t he ne xt d ose le vel has bee n d oc u me nte d.
6. 5
N o ni n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
N ot a p plica ble.
6. 6
C o nc o mit a nt Me dic ati o ns a n d T her a pies
A ll c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he eC R F, n oti n g t he na me, d ose, 
d urati o n a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y c ha n ges t o a c o nc o mita nt 
me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he eC R F .
6. 6. 1
Per mitte d Me dici nes
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y t he cli nical trial pr ot oc ol) t hat are c o nsi dere d 
necessar y  f or t he s u bjects’ welfare a n d will n ot i nterfere wit h t he trial me dicati o n ma y be gi ve n at 
t he In vesti gat or’s discreti o n.
T he f oll o wi n g me dicati o ns are per mitte d:

L ocal, t o pical, or s h ort -ter m (i.e., < 7 da ys) of s yste mic c ortic oster oi ds

A nti -i nfecti o us dr u gs

He mat o p oietic gr o wt h fact ors, if me dicall y i n dicate d.
T he I n vesti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y  the s u bject a n d a n y c o nc o mita nt 
pr oce d ures pr o vi de d t o t he s u bject d uri n g t he trial, fr o m t he date of si g nat ure of i nf or me d c o nse nt, 
i n t he a p pr o priate secti o ns of t he e C R F.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he trial a n d a n y cha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti on of t he e C R F, n oti n g t he na me, 
d ose, d urati o n a n d i n dicati o n of eac h dr u g.
6. 6. 2
Pr o hi bite d Me dici nes
As state d i n Secti o n 5. 3. 2 , s u bjects m ust n ot ha ve recei ve d c he m ot hera p y, i m m u n ot hera py,  
h or m o nal t hera py,  bi ol o gic t hera p y, or a n y ot her a ntica ncer t hera p y or a n y in vesti gati o nal a ge nt 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 4 9
wit hi n 2 8 da y s of t he first d ose of I M P a d mi nistrati o n ( 6 wee ks f or nitr os o ureas or mit o m yci n C), 
e xce pt f or s u bjects wit h ra pi dl y gr o wi n g t u m ors l ocalize d i n t he hea d a n d nec k re gi o n or t h ora x 
w here t he treati n g p h y sicia n ca n n ot wait f or 2 8 d a y s. T hese t hera pies are als o pr o hi bite d d uri n g 
t he treat me nt peri o d a n d u p t o 3 0 d a y s after R T, wit h t he e xce pti o n of c o nc urre nt cis plati n i n t he 
S C C H N p o p ulati o n (Ar m B). D uri n g t he treat me nt peri o d a n d u p t o 3 0 da ys after R T , a n y ot her 
i n vesti gati o nal a ge nt, c he m ot hera p y, e x te nsi ve R T (i n v ol vi n g ≥3 0 % of b o ne marr o w) or a n y o t her 
a ntica ncer t hera p y ( bi ol o gics or ot her tar gete d t hera p y) a n d a nti ne o plastic ster oi d t hera p y are als o 
pr o hi bite d ( P hase Ia a n d P hase I b o nl y) . Use of a n y in vesti gati o nal a ge nt d uri n g t he e ntire trial 
d urati o n is n ot per mitte d. 
Me dicati o ns or her bal s u p ple me nts k n o w n t o be p ote nt i n hi bit ors or i n d ucers of C Y P 3 A or 
C Y P 2 C 1 9, or dr u gs mai nl y  meta b olize d b y C Y P 3 A wit h a narr o w t hera pe utic i n de x as j u d ge d b y 
t he I n vesti gat or (a n d after o pti o nal c o ns ultati o n wit h t he S p o ns or) are p r o hi bite d (see Secti o n 6. 6. 4
f or details).
T he s ol u bilit y of M 3 8 1 4
is p H de pe n de nt; t heref ore, a ntaci d dr u gs, H 2-bl oc ker a n d P PI s mi g ht 
affect a bs or pti o n. H 2-bl oc kers or P PI s s h o ul d be st o p pe d 5 da y s pri or t o t he first treat me nt, a n d 
a v oi de d d uri n g t he e ntire treat me nt peri o d wit h I M P. A ntaci d dr u gs s h o ul d n ot be ta ke n 1 h o ur 
bef ore I M P a d mi nistrati o n u ntil 2 h o urs after I M P a d mi nistrati o n.
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he treat me nt 
peri o d , e. g., d ue t o A Es, t he s u bject s h o ul d be disc o nti n ue d fr o m t he trial treat me nt a n d c o m plete 
all assess me nts liste d u n der t he E T T visit .
See als o Secti o n 6. 6. 4 f or details of p ossi ble dr u g -dr u g i nteracti o ns wit h a n d b y  co nc o mita nt 
me dicati o n.
6. 6. 3
Ot her I nter ve nti o ns
T he pla n ni n g of R T will be i n acc or da nce wit h l ocal practice. 
P h ase I a: s u bjects will recei ve fracti o nate d palliati ve R T (Ar m A; 3 G y
x 1 0, 5 F/ W) or 
fracti o nate d R T (Ar m B; 2 G y  x 3 3 t o 3 5, 5 F/ W) as part of c urati vel y i nte n de d C R T ( wit h 
c o nc urre nt cis plati n) .
P h ase I b: N S C L C s u bjects will recei ve fracti o nate d R T ( 2 G y  x 3 3, 5 F/ W) ; S C C H N s u bjects will 
recei ve t he sa me C R T re gi me n as i n P hase Ia.
Misse d fracti o n(s) of R T m ust be gi ve n at t he e n d of t he sc he d ule t o e ns ure t hat t he t otal d ose is 
reac he d. T he d ose of M 3 8 1 4
s h o ul d be a d mi nistere d 1. 5 h o urs ( ± 3 0 mi n utes) bef ore R T . W her e 
a p plica ble, cis plati n s h o ul d be a d mi nistere d acc or di n g t o i nstit uti o nal g ui deli nes
(see 
Secti o n 6. 3. 1. 1) .
A ncill ar y c P o P p art : s u bjects will recei ve a si n gle hi g h d ose of R T ( 1 0-2 5 G y ) o n Da y 1 gi ve n 
o n L esi o n 1 a n d a si n gle hi g h d ose of R T ( 1 0 - 2 5 G y ) o n Da y  2 gi ve n o n Lesi o n 2.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 4 9
6. 6. 3. 1
R a di ot her a p y Tr e at me nt Del a y
T he f or mal criteria f or m o dificati o n of R T treat me nt are prese nte d i n  Ta ble 1 3 . Wit hi n t his trial, a 
ma xi m u m dela y  of u p t o a n d i ncl u di n g 7 d a y s i n t otal is all o we d wit hi n t he c o m plete treat me nt 
peri o d. If R T a n d I MP treat me nt ha ve t o be dela y e d b y  more t ha n 7 da ys , t he s u bject m ust be 
disc o nti n ue d fr o m I M P.
6. 6. 5
M a n a ge me nt 
of S pecific A d verse E ve nts or A d verse Dr u g 
Re acti o ns
At t he c urre nt sta ge of de vel o p me nt t here are n o k n o w n A D Rs or s pecific A Es . 
Earl y a n d late to xicities relate d t o R T a n d/ or M 3 8 1 4
will be ma na ge d acc or di n g t o t he l ocal 
i nstit ute’s g ui deli nes .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 4 9
O ver d os e of cis plati n ge nerall y res ults i n se vere f or ms of n or mall y occ urri n g a d verse reacti o ns. 
I n vesti gat ors are as ke d t o c hec k t he res pecti ve i nf or mati o n i n t he S m P C f or f urt her a d vice.
6. 7
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
M 3 8 1 4
will be pac ka ge d as b o xes of 
 pac ks of 1 0 m g , 5 0 m g  or 1 0 0 m g ca ps ules or 5 0 m g 
ta blets. 
P ac ka gi n g a n d la beli n g will be i n acc or da nce wit h all a p plica bl e l ocal re g ulat or y re q uire me nts a n d 
a p plica ble G o o d M a n ufact uri n g P ractice G ui deli nes.
6. 8
Pre p ar ati o n, H a n dli n g , a n d St or a ge of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
M 3 8 1 4
s h o ul d be st ore d at t he rec o m me n de d te m perat ure 
. A n y de viati o ns fr o m t he 
rec o m me n de d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o t he c o ntact s pecifie d i n t he 
M a n ual of O perati o ns , a n d t he trial dr u g s h o ul d n ot be use d u ntil a ut h orizati o n has bee n recei ve d 
fr o m t he S p o ns or or C R O .
T he I n vesti gat or or a trai ne d desi g nee will dis pe nse M 3 8 1 4
t o s u bjects acc or di n g t o t heir all ocate d 
d ose le vel.
Cis plati n will be st ore d acc or di n g t o t he pac ka ge i nsert a n d t he S m P C.
6. 9
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he I n vesti gat or is res p o nsi ble f or e ns uri n g acc o u nta bilit y f or M 3 8 1 4, i ncl u di n g r ec o nciliati o n of 
dr u gs a n d mai nte na nce of rec or ds.

U p o n recei pt of M 3 8 1 4 , t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y  an d 
ac k n o wle d ge recei pt b y  si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me ntati o n pr o vi de d 
b y  t he S p o ns or/ C R O a n d ret ur ni n g it t o t he l ocati o n s pecifie d. A c o p y will be arc hi ve d f or t he 
I n vesti gat or Site File.

I M P dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y  for ms pr o vi de d b y  t he 
S p o ns or / C R O s o t hat acc urate rec or ds will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

Trial site I MP acc o u nta bilit y  rec or ds will i ncl u de t he f oll o wi n g:

C o nfir mati o n of I MP recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge

T he i n ve nt or y  of I M P pr o vi de d f or t he cli nical trial a n d pre pare d at t he site

T he use of eac h d ose b y eac h s u bject

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n use d I M P

Dates, q ua ntities, batc h n u m bers, vial n u m bers, e x pir y dates, f or m ulati o n (f or I M P pre pare d 
at t he site), a n d t he i n di vi d ual s u bject trial n u m bers.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 4 9
T he I n vesti gat or site s h o ul d mai ntai n rec or ds, w hic h
a de q uatel y d oc u me nt t hat s u bjects were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d t hat all IM Ps pr o vi de d were f ull y rec o ncile d.
U n use d I M P m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he prese nt trial. A n y I M P 
t hat has bee n dis pe nse d t o a s u bject m ust n ot be re dis pe nse d t o a differe nt s u bject.
T he S p o ns or M o nit or will peri o dicall y  collect t he I M P acc o u nta bilit y for ms a n d will c hec k all 
ret ur ns ( b ot h u n use d a n d use d c o ntai ners) bef ore a uth orizi n g t heir destr ucti o n b y  t he trial site.
6. 1 0
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce
M 3 8 1 4
will be a d mi nistere d at t he site b y  the I n vesti gat or or desi g nate d pers o n nel . M 3 8 1 4
a d mi nistrati o n , i ncl u di n g batc h n u m bers, kit n u m bers, a n d vial n u m bers m ust be rec or de d i n t he 
e C R F, as a p plica ble.
Dr u g a d mi nistrati o n rec or ds will be use d t o assess c o m plia nce.
T he In vesti gat or is res p o nsi ble f or t he c o ntr ol of dr u gs u n der i n vesti gati o n; a de q uate rec or ds of 
t he recei pt ( e. g., Dr u g Recei pt Rec or d) a n d dis p ositi o n (e. g., Dr u g Acc o u nta bilit y  Rec or d, Dr u g 
Destr ucti o n Rec or d) of t he I M P, i ncl u di n g dates, q ua ntities, a n d use b y  su bject, m ust be 
mai ntai ne d.
All rec or ds a n d dr u g s u p plies m ust be a vaila ble f or i ns pecti o n at e ver y  m o nitori n g visit. O nce t he 
trial has bee n ter mi nate d a n d dr u g acc o u nta bilit y has bee n satisfact oril y co m plete d b y  th e 
p har macist or trial dr u g pre parer ( or desi g nee), t he use d a n d u n use d I M P (i.e., e m pt y, partiall y 
use d, a n d u n use d c o ntai ners) will be release d f or l ocal destr ucti o n f oll o wi n g t he i nter nal sta n dar d 
o perati n g pr oce d ures of t he desi g nate d facilit y. T he c o m plete d Dr u g Acc o u nta bilit y  an d Dr u g 
Destr ucti o n Rec or ds will be se nt t o t he m o nit or or its desi g nee.
T he site p har macist or trial dr u g pre parer ( or desi g nee) m ust mai ntai n rec or ds of t he deli ver y  of 
t he I MP t o t he trial site, t he i n ve nt or y at t he site, t he use b y  eac h s u bject a n d I MP destr ucti o n at 
t he cli nical site after dr u g acc o u nta bilit y has bee n perf or me d b y  the res p o nsi ble m o nit or. T he 
dr u g - dis pe nsi n g l o g m ust be ke pt c urre nt, listi n g t he i de ntificati o n of t he s u bject w h o recei ve d 
I M P al o n g wit h t he date a n d q ua ntit y of I M P dis pe nse d; it m ust be a vaila ble f or m o nit ori n g.
Rec or ds s hall als o be mai ntai ne d b y  the I n vesti gat or of t he met h o d of destr ucti o n (ta ki n g i nt o 
acc o u nt t he re q uire me nts of l ocal la w), a n d t he pers o n w h o dis p ose d of t he trial dr u g. T h e 
te m perat ure of t he st ora ge facilities will be m o nit ore d a n d d oc u me nte d.
After c o m pleti o n of t he trial, a n y IM P distri b ute d t o t he site b ut n ot a d mi nistere d or dis pe nse d t o 
or ta ke n b y  the s u bject will be destr o ye d at t he site. All u n use d me dicati o ns will be caref ull y 
rec or de d a n d d oc u me nte d bef ore destr ucti o n. T he In vesti gat or will e ns ure t hat t he trial dr u g s u p ply 
is n ot use d f or a ny p ur p ose ot her t ha n t h e c urre nt trial.
6. 1 1
Bli n di n g
T his is a n o pe n la bel trial; t heref ore, n o bli n di n g will be perf or me d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 4 9
6. 1 2
E mer ge nc y U n bli n di n g
N ot a p plica ble.
6. 1 3
Tre at me nt of O ver d ose
A n o ver d ose is de fi ne d as a n y dose greater t ha n t he hi g hest dail y d ose i ncl u de d i n a cli nical trial 
pr ot oc ol or pla n ne d f or a n i n di vi d ual s u bject e nr olle d i n t he trial. E ve n if it d oes n ot meet ot her 
criteria f or a n S A E , a n y o ver d ose m ust be rec or de d i n t he trial me dicati o n secti o n of t he e C R F a n d 
re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner usi n g t he S A E Re p ort F or m, a n d f oll o wi n g t he 
pr oce d ure i n Secti o n 7. 4. 1. 4 . 
T here is n o esta blis he d treat me nt f or o ver d ose wit h M 3 8 1 4 . T he I n vesti gat or s h o ul d use cli nical 
j u d g me nt t o ma na ge a n y o ver d ose c o nsi deri n g t he prese nt i n g s ym pt o ms a n d sta n dar d e val uati o n 
res ults.
6. 1 4
Me dic al C are of S u bjects after E n d of Tri al
After a s u bject has c o m plete d t he trial or has wit h dra w n earl y, us ual treat me nt will be 
a d mi nistere d, if re q uire d, i n acc or da nce wit h t he trial site’s S o C a n d ge nerall y acce pte d me dical 
practice a n d de pe n di n g o n t he s u bject’s i n di vi d ual me dical nee ds.
7
Tri al Pr oce d ures a n d Assess me nts
7. 1
Sc he d ule of Assess me nts
Pri or t o perf or mi n g a n y  trial assess me nts t hat are n ot part of r o uti ne me dical care f or t he s u bject, 
t he In vesti gat or will o btai n writte n i nf or me d c o nse nt as descri be d i n Secti o n 9. 2.
C o m plete sc he d ules of assess me nts f or P hase Ia ( Ar m A – Ca ps ule a n d Ta blet ), P hase I b – f irst 
3 s u bjects (Ar m A, N S C L C c o h ort), P hase I b (Ar m A, N S C L C c o h ort), P hase Ia ( Ar m B, S C C H N 
c o h ort), P hase I b (Ar m B, S C C H N c o h ort) a n d a ncillar y c P o P part s are pr o vi de d i n Ta ble 1,  
Ta ble 2, Ta ble 3 , Ta ble 4, Ta ble 5 , Ta ble 6 a n d Ta ble 7, res pecti vely . D uri n g R T, n o visit wi n d o w 
will be all o we d. 
E ver y  eff ort s h o ul d be ma de t o perf or m assess me nts as cl ose as p ossi ble t o t he sc he d ule d ti me 
p oi nts.
7. 1. 1
Scree ni n g Peri o d ( D a y -2 1 t o D a y -1)
Base d o n t he fi n di n gs o btai ne d d uri n g t he Scree ni n g Peri o d, t he I n vesti gat or will deci de w het her 
t he s u bject is eli gi ble f or t he trial. Sc he d ule d scree ni n g assess me nts i n all s u bjects are as f oll o ws:

Pr o visi o n of writte n i nf or me d c o nse nt f or t he trial a n d P G x a nal ysis a n d re vie w of i ncl usi o n 
a n d e xcl usi o n criteria

D oc u me ntati o n of de m o gra p hics, rele va nt me dical hist or y , a n d c o nc o mita nt me dicati o ns
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 4 9

Safet y  la b orat or y (he mat ol o g y , ser u m c he mistr y, uri nal y sis, c oa g ulati o n a n d ser u m β- h u ma n 
c h ori o nic g o na d otr o pi n [ H C G] pre g na nc y  test [if a p plica ble])

I nfecti o n scree n. He patitis B a n d C testi n g t o be perf or me d u nless o btai ne d wit hi n 3 m o nt hs 
pri or t o Scree ni n g. Scree ni n g f or HI V will be perf or me d acc or di n g t o l ocal practic e a n d l ocal 
re g ulat or y g ui da nce

E val uati o n of h u ma n pa pill o ma vir us stat us i n t u m or material b y  im m u n o hist oc he mistr y
( P hase Ia, Ar m B a n d P hase I b, Ar m B e x pa nsi o n c o h ort o nl y)

A u di o gra m, as nee de d acc or di n g t o l ocal g ui deli nes ( P hase Ia, Ar m B a n d P hase I b, Ar m B 
e x pa nsi o n c o h ort o nl y)

Assess me nt of vital si g ns ( bl o o d press ure a n d hea rt rate), b o d y  wei g ht, a n d hei g ht , b o d y  
te m perat ure ( hei g ht meas ure d at Scree ni n g o nly)

Assess me nt of A Es

T u m or e val uati o n b y  ra di o gra p hic or ot her m o dalit y  (R E CI S T v 1. 1) ( P hase Ia a n d P hase I b 
o nl y ). Baseli ne t u m or e val uati o n ca n be u p t o 2 8 da ys ol d w he n treat me nt starts

E C O G P S

1 2- lea d E C G i ncl u di n g t he Fri dericia-c orrecte d Q T i nter val ( Q Tc F )

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa) ( P hase Ia a n d P hase I b o nly) .

I n case of cli nical si g ns of es o p ha gitis, a n es o p ha geal e n d osc o p y m ust be perf or me d , if t he 
ra diati o n fiel ds i n v ol ve t he es o p ha g us.
A ncillar y  c P o P part of t he trial o nl y :

E val uati o n of all tiss ues i n t he R T area

L ocal t u m or assess me nt (i n irra diate d lesi o ns) b y  cli nical e xa m or i ma gi n g acc or di n g t o 
R E CI S T v 1. 1 ( o nl y a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 f or m ulati o n]).
7. 1. 2
Tre at me nt Peri o d
7. 1. 2. 1
P h ase I a P art : Ar m A a n d Ar m B ( Fr acti o n D a ys 1 t o 1 0)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y s 1, 6 a n d 1 0; if Fracti o n Da y 1 0 is 
o n a Fri da y , P K, 
 safet y la b orat or y, a n d uri nal ysis sa m pli n g m ust be d o ne o n Fra cti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 4 9

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area ( Fracti o n Da y  6 a n d 1 0 o nly)

E C O G P S ( Fracti o n Da y 1 0 o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 1 0 o nl y)

1 2- lea d E C G i ncl u di n g Q Tc F ( Fracti o n Da y 1 a n d 1 0)

C ollecti o n of P K bl o o d s a m ples

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y  s h o ul d be ta ke n
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y 2:

C ollecti o n of P K bl o o d sa m ples ( pre d ose)
7. 1. 2. 2
P h ase I a P art : Ar m B ( S C C H N) ( Fr acti o n D a ys 1 6 t o 3 1)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da y s 1 6, 2 1, 2 6, 3 1, a n d last F D/ E T T 

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area

E C O G P S ( last Fracti o n Da y  o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 4 9

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 16 a n d last Fracti o n Da y o nl y )

1 2-lea d E C G i ncl u di n g Q Tc F
7. 1. 2. 3
P h ase I b P art : Ar m A ( N S C L C) E x p a nsi o n C o h ort ( Fr acti o n 
D a ys 1 t o 3 3)
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da ys 1, 6 (first 3 s u bjects o nl y), 1 0, 16 , 
2 1 , 26 a n d 3 3 ; if Fracti o n Da y 1 0 is o n a Fri da y , P K, P D, a n d safet y la b orat or y sa m pli n g m ust be 
d o ne o n Fracti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area ( n ot perf or me d o n Fracti o n Da y  1)

E C O G P S ( Fracti o n Da y  3 3 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da ys 1 0 [f irst 3 s u bjects o nl y ], 1 6, a n d 3 3 o nl y )

1 2- lea d E C G i ncl u di n g Q Tc F ( Fracti o n Da y 1 a n d 1 0)

C ollecti o n of P K bl o o d sa m ples ( Fracti o n Da y s 1 a n d 1 0 o nl y)

A vaila bilit y  of arc hi val t u m or material, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y s h o ul d be ta ke n
T he f oll o wi n g assi g n me nts will be perf or me d o n Fracti o n Da y 2 (first 3 s u bjects o nl y):

C ollecti o n of P K bl o o d sa m ples ( pre d ose)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 4 9
7. 1. 2. 4
P h ase I b P art : Ar m B ( S C C H N) E x p a nsi o n C o h ort ( Fr acti o n 
D a ys 1 t o L ast Fr acti o n D a y )
Eli gi ble s u bjects will recei ve M 3 8 1 4
d uri n g t he peri o d i n w hic h C R T is gi ve n.
T he f oll o wi n g assess me nts will be perf or me d o n Fracti o n Da ys 1, 6, 1 0, 1 6 , 21 , 26, 3 1 a n d t he last 
Fracti o n D a y ( 3 3 t o 3 5) ; if Fracti o n D a y 1 0 is o n a Fri da y, P K, 
 a n d safet y la b orat or y sa m pli n g 
m ust be d o ne o n Fracti o n Da y 9:

Re vie w of i ncl usi o n a n d e xcl usi o n criteria ( Fracti o n Da y  1 o nl y)

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details)

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all ti ss ues i n t he R T area ( n ot perf or me d o n Fracti o n Da y 1)

E C O G P S ( last Fracti o n Da y  o nl y)

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

Uri nal y sis ( Fracti o n Da y 1 6 a n d last Fracti o n Da y o nl y )

1 2-lea d E C G i ncl u di n g Q Tc F

C ollecti o n of P K bl o o d sa m ples ( Fracti o n Da y s 1 a n d 1 0 o nl y)

A vaila bilit y  of arc hi val t u m or materi al, eit her as a bl oc k or sli des. If n o arc hi val material is 
a vaila ble t he n a fres h bi o ps y  s h o ul d be ta ke n
7. 1. 2. 5
A ncill ar y c P o P P art
Eli gi ble s u bjects will recei ve a si n gle hi g h d ose of R T gi ve n o n L esi o n 1 o n Da y 1, a n d o n Da y 2, 
will recei ve M 3 8 1 4
wit h a si n gle hi g h d ose of R T gi ve n o n Lesi o n 2 .
F or l o gistical reas o ns ( ha n dli n g a n d se n di n g materials), Da y 1 m ust be o n a We d nes da y or earlier.
T he f oll o wi n g assess me n ts will be perf or me d o n Da y 1 a n d Da y 2:

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o d y te m perat ure), b o d y wei g ht (see 
Secti o n 7. 4. 4 f or details).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 4 9

E val uati o n of all tiss ues i n t he R T area ( Da y  2 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

T u m or bi o ps y :
o
D a y  1: baseli ne bi o psy t o be ta ke n a n y t i me pri or t o R T f or b ot h lesi o ns ( Scree ni n g 
t o Da y 1) a n d 2-4 h o urs after R T f or Lesi o n 1
o
D a y  2: t o be ta ke n 2- 4 h o urs after R T f or Lesi o n 2.
7. 1. 3
F oll o w -u p Peri o d
7. 1. 3. 1
D L T Peri o d : P h ase I a, Ar m A
T he f oll o wi n g assess me nts will be perf or me d o n P T D 8 a n d 1 5 :

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o dy te m perat ure ), bo d y  wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n) 

Uri nal y sis.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 4 9
7. 1. 3. 2
D L T Peri o d /S h ort -ter m S afet y F oll o w -u p : P h ase I a, Ar m B
a n d First 3 S u bjects i n P h ase I b ( Ar m A E x p a nsi o n C o h ort i n 
N S C L C)
T he f oll o wi n g assess me nts will be perf or me d o n P T D 7, 1 4, 2 1, 2 8 a n d 3 5 ( P hase Ia, Ar m B) or 
o n P T D 8, 1 5, 2 2 a n d 3 7 (first 3 s u bjects i n P hase I b, Ar m A) :

Ser u m β -H C G pre g na nc y  test (if a p plica ble a n d o nl y  PT D 2 8 [ P hase Ia, Ar m B] or P T D 2 2
[first 3 s u bjects i n P hase I b, Ar m A] )

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y te m perat ure), b o d y wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g petec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n) 

Uri nal y sis.
7. 1. 3. 3
S h ort -ter m S afet y F oll o w -u p : P h ase I a, Ar m A a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 2 a n d 3 0 i n P hase Ia ( Ar m A) a n d o n 
P T D 8, 1 5, 2 2 a n d 3 0 i n P hase I b :

Ser u m β -H C G pre g na nc y test (if a p plica ble a n d o nl y P T D 3 0)

Assess me nt of vital si g ns ( bl o o d press ure , heart rate , a n d b o dy te m perat ure ), bo d y  wei g ht

P h y sical e xa mi nati o n

Cli nical e xa mi nati o n of blee di n g (i ncl u di n g pet ec hiae, i n s ki n, i n t he sclera of t he e ye, oral 
m uc osa)

E val uati o n of all tiss ues i n t he R T area 

E C O G P S (P T D 3 0 o nl y )

Assess me nt of A Es

D oc u me ntati o n of c o nc o mita nt me dicati o ns

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati on) 

Uri nal y sis (P T D 3 0 o nl y) .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 4 9
7. 1. 3. 4
Mi d -ter m S afet y F oll o w-u p : P h ase I a a n d P h ase I b
T he mi d -ter m safety f oll o w- u p will be perf or me d o n P T D 8 4. T o e val uate si g ns of R T -i n d uce d 
t o xicit y o n n or mal s urr o u n di n g tiss ues, t he f oll o wi n g assess me nts were perf or me d:

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht
( P hase Ia o nly)

P h y sical e xa mi nati o n

1 2- lea d E C G i ncl u di n g Q Tc F ( Ar m B S C C H N c o h ort o nl y)

E C O G P S

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A E s
7. 1. 3. 5
L o n g -ter m S afet y F oll o w -u p : P h ase I a a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d f or all s u bjects, e xcl u di n g s u bjects i n t he a ncillar y 
c P o P part of t he trial, o n P T D 4 2, 1 2 6, 1 6 8, a n d 1 8 0, ( P hase Ia a n d P hase I b), a n d o n P T D 2 7 0 a n d 
3 6 5 ( P ha se I b o nly) :

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y te m perat ure), b o d y wei g ht

P h y sical e xa mi nati o n 

1 2- lea d E C G i ncl u di n g Q Tc F ( Ar m B S C C H N c o h ort o nl y)

E C O G P S

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A Es

T u m or assess me nt acc or di n g t o R E CI S T v 1. 1, o nl y  re q uire d if s u bject has n ot starte d a ne w 
a ntit u m or treat me nt. If a ne w treat me nt is starte d, t he date (a n d re gi me n) m ust be re p orte d i n 
e C R F. 
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 1 0 a n d 3 1 2:

E val uati o n of l o n g ter m R T t o xicit y (s u bject calle d b y p h o ne).
7. 1. 3. 6
S ur vi v al F oll o w -u p : P h ase I a a n d P h ase I b
T he f oll o wi n g assess me nts will be perf or me d o n P T D 2 7 0 a n d 3 6 5 ( E O T) f or patie nts i n P hase Ia, 
Ar m A :

Assess me nt of vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht. O nl y 
re q uire d f or P hase Ia if s u bject has n ot starte d a ne w a ntit u m or treat me nt

P h y sical e xa mi nati o n

E C O G P S
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 4 9

E val uati o n of all tiss ues i n t he R T area 

E val uati o n of o n g oi n g T E A Es

T u m or assess me nt acc or di n g t o R E CI S T v 1. 1. O nl y  re q uire d f or P hase Ia if s u bject has n ot 
starte d a ne w a ntit u m or treat me nt.
F or all patie nts, the s ur vi val f oll o w- u p peri o d will c o nti n ue u ntil 1 2 m o nt hs after t he last s u bject 
has st o p pe d R T/ C R T ( defi ne d as e n d of trial; see Secti o n 5. 7) . After c o m pleti o n of t he visit o n 
P T D 3 6 5, all s u bjects will be f oll o we d f or s ur vi val e ver y 3 mo nt hs via a p h o ne call u ntil t he e n d 
of t he trial.
7. 1. 3. 7
F oll o w -u p f o r t he A ncill ar y c P o P P art of t he Tri al
T he f oll o wi n g assess me nts will be perf or me d o n Da y  1 0 a n d Da y  32 ( 8 a n d 3 0 d a y s after e n d of 
treat me nt):

Assess me nt of vital si g ns ( bl o o d press ure , heart rate, a n d b o d y  te m perat ure), bo d y  wei g ht
( Da y 1 0 o nl y)

E val uati o n of all tiss ues i n R T area

Assess me nt of A Es (l ocal t olera bilit y 3 0 da ys after last trial dr u g a d mi nistrati o n )

D oc u me ntati o n of c o nc o mita nt me dicati o ns ( o nl y at Da y 1 0)

Safet y  la b orat or y ( he mat ol o g y, ser u m c he mistr y a n d c oa g ulati o n)

L ocal t u m or assess me nt (i n irra diate d lesi o ns) b y  cli nical e xa m or i ma gi n g acc or di n g t o
R E CI S T v 1. 1 ( o nl y at Da y 1 0 a n d o nl y a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 
f or m ulati o n]).
7. 1. 4
Disc o nti n u ati o n/ E n d of Tri al
F or t he P hase Ia a n d I b parts, all s u bjects w h o disc o nti n ue I MP m ust u n der g o a f ull safety 
e val uati o n at t he ti me of disc o nti n uati o n. T he assess me nts s pecifie d f or t he E T T visit s h oul d be 
perf or me d (see Ta ble 1 [ P hase Ia – Ar m A ca ps ule c o h orts ], Ta ble 2 [ P hase Ia – Ar m A ta blet 
c o h orts],
Ta ble 3
[first 3 s u bjects i n P hase I b
–
Ar m A, 
N S C L C 
c o h ort],
Ta ble 4
[ P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia – Ar m B, S C C H N c o h ort] a n d Ta ble 6
[ P hase Ib – Ar m B, S C C H N c o h ort] f or details).
A n E O T v isit will als o be perf o r me d o n P T D 3 6 5, or if t he s u bject wit h dra ws pri or t o P T D 3 6 5 . 
A ll assess me nts m ust be d o ne as pla n ne d f or t he EO T visit, see Secti o n s 7. 1. 3. 5 a n d 7. 1. 3. 6.
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
T he assess me nts a n d pr oce d ures descri be d i n t his secti o n m ust be perf or me d d uri n g t he Scree ni n g 
Peri o d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 4 9
7. 2. 1
De m o gr a p hic D at a
T he f oll o wi n g de m o gra p hic data will be rec or de d:

S u bject i de ntifier

Date of birt h

Se x

Race

Et h nicit y
7. 2. 2
T u m or Hist or y
T he f oll o wi n g i nf or mati o n will be d oc u me nte d a n d verifie d at t he S cree ni n g visit f or eac h s u bject:

All t hera py use d f or pri or treat me nt of t he t u m or (i ncl u di ng s ur ger y, R T , c he m ot hera p y, 
i m m u n ot hera p y, a n d h or m o nal or bi ol o gic t hera p y)

C urre nt ca ncer si g ns a n d s ym pt o ms a n d si de effects fr o m c urre nt a n d/ or pre vi o us a ntica ncer 
treat me nts

Date of dia g n osis a n d hist ol o g y , w he ne ver p ossi ble

Gra di n g a n d sta gi n g of t he t u m or

Date of t he first occ urre nce of disease a n d t he date of pr o gressi o n after t he first, sec o n d, a n d 
a n y s u bse q ue nt treat me nt fail ure.

H u ma n pa pill o ma vir us e val uati o n i n S C C H N t u m or material (f or P hase Ia, Ar m B a n d P hase I b, 
S C C H N e x pa nsi o n c o h ort o n l y)
7. 2. 3
Me dic al Hist or y
a n d Pre vi o us a n d C o nc o mit a nt Me dic ati o n
T o deter mi ne t he s u bject’s eli gi bilit y  f or t he trial, rele va nt me dical hist or y of eac h s u bject will be 
c ollecte d a n d d oc u me nte d d uri n g scree ni n g t hat will i ncl u de t he f oll o wi n g:

Past a n d c o nc o mit a nt n o n mali g na nt diseases a n d treat me nts

All me dicati o ns ta ke n a n d pr oce d ures carrie d o ut wit hi n 2 1 da y s pri or t o scree ni n g.
F or trial e ntr y , all s u bjects m ust f ulfill all i ncl usi o n criteria descri be d i n Secti o n 5. 3. 1 a n d n o ne of 
t he e xcl usi o n criteria descri be d i n Secti o n 5. 3. 2.
7. 2. 4
Vit al Si g ns a n d P h ysic al E x a mi n ati o n
Vital si g ns, i ncl u di n g b o d y  te m perat ure, heart rate a n d bl o o d press ure (after 5 mi n ute s rest), will 
be rec or de d at trial e ntr y .
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g ge neral a p peara nce, der mat ol o gical, hea d/ nec k, 
p ul m o nar y , car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, m usc ul os keletal s yste m, 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 4 9
e xtre mities, e yes [i ns pecti o n a n d visi o n c o ntr ol], n ose, t hr oat, a n d ne ur ol o gic stat us) will be 
perf or me d a n d t he res ults d oc u me nte d.
Cli ni cal e xa mi nati o n of blee di n g (i ncl u di n g petec hiae , i n s ki n, i n t he sclera of t he e ye, oral m uc osa)
will be perf or me d .
T he E C O G P S will be d oc u me nte d d uri n g t he Scree ni n g Peri o d.
B o d y wei g ht a n d hei g ht will be rec or de d.
7. 2. 5
C T 
or M a g netic 
Res o n a nce 
I m a gi n g Sc a ns f or T u m or 
Assess me nt
A n e n ha nce d C T sca n or e n ha nce d ma g netic res o na nce i ma gi n g ( M RI) of t he t u m or will be 
perf or me d pri or t o t he be gi n ni n g of trial treat me nt t o d oc u me nt t he baseli ne stat us of t he t u m or 
usi n g R E CI S T v 1. 1 (A p pe n di x B ). Baseli ne t u m or e val uati o n ca n be u p t o 2 8 d a y s ol d w he n 
treat me nt starts.
7. 2. 6
C ar di ac Assess me nts
Tri plicate 1 2- lea d E C Gs will be rec or de d l ocally at scree ni n g ( pred ose) after t he s u bject has bee n 
i n a s u pi ne p ositi o n breat hi n g q uietly f or at least 5 mi n utes a n d p ost d ose. T he E C G res ults will be 
use d t o e val uate t he heart rate, atrial ve ntric ular c o n d ucti o n, Q R a n d Q T i nter vals (i ncl u di n g 
Q Tc F), a n d p ossi ble arr h y t h mias.
7. 2. 7
Cli nic al L a b or at or y Tests
Bl o o d sa m ples will be c ollecte d l ocall y at scree ni n g f or cli nical la b orat or y para meter e val uati o ns. 
T hese cli nical la b orat or y test res ults will ser ve n ot o nl y  as t he baseli ne val ues f or s u bse q ue nt safety 
cli nical la b orat or y eval ua ti o ns d uri n g t he trial b ut als o as verificati o n t hat eac h e nr olle d s u bject 
f ulfills all t he trial e ntr y criteria a n d d oes n ot meet a n y of t he trial e xcl usi o n criteria f or la b orat or y 
para meters as liste d i n Secti o n 5. 3. 2 . Detaile d descri pti o n of la b orat or y assess me nts is pr o vi de d i n 
Secti o n 7. 4. 3.
7. 3
Effic ac y Assess me nts
7. 3. 1
T u m or Res p o nse Assess me nt
T u m or res p o nse will be e val uate d acc or di n g t o R E CI S T v 1. 1 (see A p pe n di x B ).
T he t u m or res p o nse assess me nt will be perf or me d as liste d acc or di n g t o t he sc he d ules of 
assess me nts (Ta ble 1 [ P hase Ia – Ar m A
ca ps ule c o h orts ], Ta ble 2 [P hase Ia – Ar m A ta blet 
c o h orts],
Ta ble 3
[first 3 
s u bjects i n P hase I b
–
Ar m A, 
N S C L C 
c o h ort],
Ta ble 4
[ P hase I b – Ar m A, N S C L C c o h ort], Ta ble 5 [ P hase Ia – Ar m B, S C C H N c o h ort] a n d Ta ble 6
[ P hase Ib – Ar m B, S C C H N c o h ort] ). T his s h o ul d i ncl u de a c o m plete assess me nt of all tar get a n d 
n o ntar get lesi o ns f or s u bjects wit h s oli d t u m ors. T his assess me nt will be perf or me d b y  CT or M RI . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 4 9
I n ge neral, lesi o ns detecte d d uri n g scree ni n g nee d t o be f oll o we d usi n g t he sa me met h o d ol o g y  an d 
prefera bl y t he sa me e q ui p me nt at s u bse q ue nt t u m or assess me nt v isits.
F or t he a ncillar y cP o P part of t he trial ( o nly a p plica ble f or a d diti o nal c o h orts of M 3 8 1 4 [ 
 
f or m ulati o n]): T he l ocal t u m or res p o nse assess me nt i n irra diate d lesi o ns will be perf or me d as liste d 
acc or di n g t o t he sc he d ule of assess me nts (Ta ble 7) . L o cal t u m or res p o nse i n irra diate d lesi o ns will 
be e val uate d acc or di n g t o R E CI S T v 1. 1 (see A p pe n di x B ). T his assess me nt will be perf or me d 
f oll o wi n g t he i nstit uti o nal practices, eit her b y  cli nical e xa m or i ma gi n g. Lesi o ns assesse d d u ri n g 
scree ni n g nee d t o be f oll o we d b y  the sa me tec h ni q ue a n d met h o d ol o g y  of assess me nt at t he 
s u bse q ue nt t u m or assess me nt visit o n Da y 1 0. T he c uta ne o us a n d s u bc uta ne o us lesi o ns s h o ul d als o 
be d oc u me nte d b y c ol or p h ot o gra p h y (i ncl u di n g a cali per or scale ) at Baseli ne a n d o n Da y 1 0.
7. 4
Assess me nt of S afet y
T he safety pr ofile of M 3 8 1 4
will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d a nal ysis of 
baseli ne me dical c o n diti o ns, A Es , p h y sical e xa mi nati o n fi n di n gs i ncl u di n g vital si g ns a n d 
m o nit ori n g f or blee di n g, la b orat or y tests, E C O G P S , a n d 1 2- lea d E C Gs.
C o m pre he nsi ve assess me nt of a n y ap pare nt t o xicit y ex perie nce d b y  eac h s u bject will be perf or me d 
fr o m t he ti me of gi vi n g i nf or me d c o nse nt u p t o 1 2 m o nt hs after R T c o m pleti o n . T he I n vesti gat or
will re p ort a n y A Es , w het her o bser ve d b y  the I nvesti gat or or re p orte d b y  the s u bject (see 
Secti o n 7. 4. 1. 2) . T he re p orti n g peri o d f or A E s is descri be d i n Secti o n 7. 4. 1. 3 .
7. 4. 1
A d verse E ve nts
7. 4. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. A n 
A E ca n t heref ore be a n y unfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n ab n or mal la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct. 
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ur e is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself. T he I n vesti gat or is re q uire d t o gra de t he 
se verity or t o xicit y of eac h A E .
I n vesti gat ors will refere nce t he Nati o nal Ca ncer I nstit ute ( N CI)-C T C A E, v 4. 0 3 ( p u blicati o n date: 
1 4 J u ne 2 0 1 0 ), a descri pti ve ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; hereafter referre d t o as se verity ) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 4 9
If a partic ular A E se verit y is n ot s pecificall y gra de d b y t he g ui da nce d oc u me nt, t he I n vesti gat or is 
t o use the ge neral N CI -C T C A E ( v 4. 0 3) defi niti o ns of Gra de 1 t hr o u g h Gra de 5 f oll o wi n g his or 
her best me dical j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g

Gra de 5 or Deat h .
Acc or di n g t o t he S p o ns or’s c o n ve nti o n, a n y cli nical A E wit h se verity of Gra de 4 or 5 m ust als o 
be re p orte d as a n S A E. H o we ver, a la b orat or y a b n or malit y of Gra de 4, s uc h as a ne mia or 
ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he c o n diti o n meets o ne of t he seri o us criteria descri be d 
bel o w.
If deat h occ urs , t he pri mar y  ca use of deat h or t he e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be re c or de d as t he o utc o me of t h is s pecific e ve nt a n d deat h will 
n ot be rec or de d as a se parate e ve nt. O nl y i f n o ca use of deat h ca n be re p orte d (f or e xa m ple, s u d de n 
deat h, u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o t he trial treat me nt
usi n g t he f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E 
t o M 3 8 1 4 / R T/ C R T i ncl u de te m p oral relati o ns hi p bet wee n t he A E a n d M 3 8 1 4 / R T/ C R T, k n o w n 
si de effects of M 3 8 1 4 / R T/ C R T, me dical hist or y , c o nc o mita nt me dicati o n, c o urse of t he u n derl y i n g 
disease, trial pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o M 3 8 1 4 / R T/ C R T treat me nt. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o M 3 8 1 4 / R T/ C R T treat me nt u n der 
st u d y in t his cli nical trial pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be 
a vaila ble.
Rel ate d:
R eas o na bl y 
relate d 
t o M 3 8 1 4 / R T/ C R T
treat me nt. A E 
c o ul d 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o M 3 8 1 4 / R T/ C R T treat me nt u n der 
st u d y i n t his cli nical trial pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (f or e xa m ple, o n a n 
E C G trace) s h o ul d n o t be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o treat me nt disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  
t he I n vesti gat or. If a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n 
(e. g., a ne mia, i ncrease d A LT) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue itself.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 4 9
Seri o us A d verse E ve nt s
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h.

Is life-t hreate ni n g. (N ote: T he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is 
at ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca used deat h 
if it was m ore se vere. )

Re q uires i n patie nt h os pitalizati o n or pr ol o n g s a n e xisti n g h os pitalizati o n.

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacity.

Is a c o n ge nital a n o maly or birt h defect.

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. ( N ote: I mp orta nt me dical e ve nts t hat ma y 
n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he s u bject or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples 
of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y 
r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, 
or t he de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. ).
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n I M P  is als o 
c o nsi dere d a n S A E as descri be d i n Secti o n 7. 4. 1. 4.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y trial treat me nt or trial pr oce d ures (f or 
e xa m ple, a n o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) 
are n ot c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (e. g., u n desira ble effects of a n y a d mi nistere d treat me nt) 
m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or fre q ue nc y duri n g 
t he trial are defi ne d as Baseli ne Me dical C o n diti o ns, a n d are N O T t o be c o nsi dere d A Es.
A Es/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n
Pr o gressi o n of t he disease/ dis or der b ei n g st u die d, assesse d b y  meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds , as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he patie nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d (as defi ne d i n Secti o n 7. 4. 1. 3 ).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 4 9
A d verse E ve nt s of S peci al I nterest f or S afet y M o nit ori n g
N ot y et defi ne d.
D ose Li miti n g T o xicities
Eac h D L T (as defi ne d i n Secti o n 7. 4. 1. 5) , re gar dless of seri o us ness m ust be i m me diatel y rec or de d 
i n t he e C R F. I n ad diti o n, seri o us D L Ts ha ve t o re p orte d i n a n e x pe dite d ma n ner as f or S A Es as 
descri be d i n Secti o n 7. 4. 1. 4 .
7. 4. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts
At eac h trial visit, t he s u bject will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d , a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, 
w het her re p orte d b y t he s u bject or o bser ve d b y t he I nvesti gat or . 
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he eC R F. 
All S A Es m ust be d oc u me nte d a d diti o nall y a n d re p orte d usi n g t he a p pr o priate f or m as descri be d 
i n Secti o n 7. 4. 1. 4.
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates [a n d ti mes w he n it is i m p orta nt t o assess t he ti me of A E o nset relati ve t o t he 
rec or de d treat me nt a d mi nistrati o n ti me]), its se verit y, its ca usal relati o ns hi p wit h t he trial 
treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or ot her acti o n ta ke n , i ncl u di n g 
d ose m o dificati o n or disc o nti n uati o n of t he I MP, a n d its o utc o me. I n a d diti o n, seri o us cases s h o ul d 
be i de ntifie d a n d t he a p pr o priate seri o us ness criteria d oc u me nte d. If a n A E c o nstit utes a D L T t his 
has t o be d oc u me nte d acc or di n gl y.
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d 
b y t he S p o ns or.
7. 4. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he s u bject is i nitiall y i ncl u de d i n t he 
trial ( date of first si g nat ure of i nf or me d c onse nt ) a n d c o nti n ues t hr o u g h t he trial’s p ost -treat me nt
f oll o w-u p peri o d u p t o P T D 3 6 5. 
A T E A E is defi ne d as a n y AE t hat occ urs fr o m t he d a y  of first d ose of M 3 8 1 4 (re gar dless of 
pretreat me nt or p ost -treat me nt o n first d osi n g da y ), t hr o u g h Da y 3 0 after t he e n d of R T. 
A n y  SA E assesse d as relate d t o M 3 8 1 4
m ust be re p orte d w he ne ver it occ urs irres pecti ve of t he 
ti me ela pse d si nce t he last a d mi nistrati o n of M 3 8 1 4 . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 4 9
7. 4. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest a n d D ose Li miti n g T o xiciti es
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 h o urs after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee i n writi n g. All writte n re p or ts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort 
F or m, w hic h m ust be c o m plete d b y  t he I n vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
I n e xce pti o nal circ u msta nces, a n S A E ( or f oll o w- u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
in t hese cases, a writ te n re p ort m ust be se nt i m me diatel y t hereafter.
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e. g., me dical hist or y , c o nc o mita nt 
me dicati o n ). A d diti o nal d oc u me nts m a y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (f or e xa m ple, 
la b orat or y res ults, h os pital re p ort a n d a ut o ps y re p ort). In all cases, t he i nf or mati o n pr o vi de d o n t he 
S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he e C R F.
T he I n vesti gat or m ust 
res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (e. g., a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  h ave o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y  to e ns ure pr o m pt assess me nt of the e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us ual l y be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e x ce pti o nal 
circ u msta nces t he C R O’s Gl o bal Dr u g Safet y de part me nt ma y  c o ntact t he I n vesti gat or directly t o 
o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
D ose Li miti n g T o xicities
Eac h e ve nt meeti n g t he criteria of a D L T (see Secti o n 7. 4. 1. 5 ) m ust be rec or de d i n t he e C R F wit hi n 
2 4 h o urs after bec o mi n g a ware of t he e ve nt. Seri o us D L Ts m ust
be re p orte d i n a n e x pe dite d 
ma n ner as S A Es as o utli ne d a b o ve .
7. 4. 1. 5
D ose Li miti n g T o xicities
A
D L T is defi ne d as a n y Gra de ≥3 n o n he mat ol o gic A E or a n y Gra de ≥4 he mat ol o gic A E 
(acc or di n g t o N CI-C T C A E v ersi o n 4. 0 3) t hat is relate d t o a n y of t he st u d y treat me nts a n d occ urs 
d uri n g t he D L T peri o d of 5 wee ks ( P hase Ia, Ar m A) or 1 2 wee ks ( P hase Ia, Ar m B a n d P hase I b, 
first 3 s u bjects i n t he e x pa nsi o n c o h ort of Ar m A [ N S C L C] ) after t he first d ose of M 3 8 1 4 .
A D L T m ust be c o nfir me d b y  t he S M C.
I n a d diti o n, t he f oll o wi n g are c o nsi dere d D L Ts:
1.
Gra de 3 t hr o m b oc y t o pe nia wit h me dicall y c o ncer ni n g blee di n g
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 4 9
2. 
F e brile ne utr o pe nia
3.  
A n y  to xicit y  or st u dy treat me nt-relate d T E A E t hat, i n t he o pi ni o n of t he S M C , is of p ote ntial 
cli nical si g nifica nce s uc h t hat f urt her d ose escalati o n w o ul d e x p ose s u bjects t o u nacce pta ble 
ris k
4.
A n y  t o xicit y relate d t o st u d y treat me nts t hat ca uses t he s u bject t o recei ve less t ha n 8 0 % of 
t he pla n ne d R T d ose
5.
A n y  t o xicit y relate d t o st u d y treat me nts lea di n g t o a n interr u pti o n of R T l o n ger t ha n 1 wee k 
i n Ar m B
6.
E vi de nce of st u d y treat me nt-relate d he pat ocell ular i nj ur y for m ore t ha n 3 da y s, s uc h as 
> 5- f ol d ele vati o ns a b o ve t he U L N of A L T or A S T ( C T C A E Gra de 3 or 4) wit h or wit h o ut 
ele vati o n of ser u m t otal bilir u bi n t o > 2 × U L N, wit h o ut i nitial fi n di n gs of c h olestasis 
(ele vate d ser u m al kali ne p h os phatase) or ot her a p pare nt cli nical ca usalit y.
T he f oll o wi n g st u d y treat me nt-relate d A Es are e xce pti o ns t o t he a b o ve me nti o ne d D L T defi niti o n 
a n d are n ot c o nsi dere d t o be D L Ts :
1.
M uc ositis ( m uc osal i nfla m mati o n), i ncl u di n g oral m uc ositis (st o matitis) of Gr a de ≥3 lasti n g 
f or ≤4 wee ks after c o m pleti o n of t he st u d y  treat me nts
2.
St o matitis ass ociate d t o xicities (e. g., s wall o wi n g d y sf u ncti o n [ o d yn o p ha gia, d y s p ha gia], 
decrease d a p petite or wei g ht l oss d ue t o diffic ult y  or pai nf ul s wall o wi n g) of Gra de ≥3 
lastin g f or ≤4 wee ks after c o m pleti o n of t he st u d y treat me nts
3.
Diarr hea of Gra de ≥3 ( ≤3 da y s d urati o n) f oll o wi n g a de q uate a n d o pti mal t hera p y 
4.
Na usea a n d v o miti n g of G ra de ≥3 ( ≤3 da y s d urati o n) wit h a de q uate a n d o pti mal t hera p y
5.
Ra diati o n der matitis a n d ass ociate d t o xicities of Gra de ≥3 lasti n g f or ≤4 wee ks after 
c o m pleti o n of t he st u d y treat me nts
6.  
N e utr o pe nia of Gra de 4 lasti n g f or ≤5 da y s a n d n ot ass ociate d wit h fe ver
7.
Is olate d Gra de 4 ly m p h oc y t o pe nia wit h o ut cli nical c orrelate
8.
Fati g ue or hea dac he of Gra de 3 ( ≤7 d a y s d urati o n) f oll o wi n g i nitiati o n of a de q uate 
s u p p orti ve care
9.
A n y  ot her si n gle la b orat or y val ues of Gra de ≥3 o ut of t he n or mal ra n ge t hat ha ve n o cli nical 
si g nifica nce, a n d t hat res ol ve t o Gra de 2 or less wit h a de q uate meas ures wit hi n 7 da y s.
T he d urati o n of fee di n g t u be ( F T) use ( nas o gastric t u be, perc uta ne o us e n d osc o pic gastr ost o m y ) 
s h o ul d n ot defi ne t he se verity of t he t o xicit y (e. g., se vere s wall o wi n g d y sf u ncti o n, na usea, 
v o miti n g). A caref ul e val uati on of t he s u bject’s s ym pt o ms b y  the I n vesti gat or at eac h visit is 
re q uire d i n or der t o i de ntif y su bjects w h o are F T de pe n de nt (e. g., s u bjects w h o ref use/a v oi d 
s wall o wi n g, etc).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 4 9

I n t he e ve nt of se vere s wall o wi n g d y sf u ncti o n ( Gra de ≥3 d y s p ha gia or o d y n o p ha gi a) t hat 
re q uires F T place me nt a n d res ol ves t o Gra de ≤2 pri or t o t he e n d of 4 wee ks after c o m pleti n g 
st u d y treat me nts, if t he F T is still i n place f or ot her reas o ns t he n dys p ha gia or o d y n o p ha gia will 
n ot be c o nsi dere d a D L T.

I n t he e ve nt of Gra de 3 na usea or Gra de ≥3 v o miti n g t hat re q uires F T place me nt a n d res ol ves 
t o Gra de ≤2 wit hi n 3 da ys, if t he F T is still i n place f or ot her reas o ns t he n na usea or v o miti n g 
will n ot be c o nsi dere d a D L T. 
T he S M C ma y  i de ntif y as a D L T, a n y A D R t hat i m pairs dail y fu ncti o n, or a b n or malit y  occ urri n g 
i n s u bjects treate d wit h M 3 8 1 4
at a n y ti me d uri n g t he trial i ncl u di n g i n-fiel d late ra diati o n 
t o xicities.
S u bjects w h o disc o nti n ue treat me nt wit h M 3 8 1 4
beca use of a D L T s h o ul d n ot be re-e x p osed t o 
t he trial dr u g b ut o n g oi n g R T ca n c o nti n ue.
S u bjects w h o d o n ot c o m plete t he D L T o bser vati o n peri o d f or reas o ns ot her t ha n a D L T will be 
re place d.
7. 4. 1. 6
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics 
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n vest i g at ors
T he S p o ns or / desi g nee will 
se n d a p pr o priate safety n otificati o ns t o Healt h 
A ut h orities 
i n 
acc or da nce wit h a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es (partic ular l y deat hs) i n v ol vi n g trial s u bjects t o t he I EC/I R B t hat a p pr o ve d t he 
trial.
I n acc or da nce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of “fi n di n gs t hat 
c o ul d a d versel y affect t he safety o f s u bjects, i m pact t he c o n d uct of t he trial or alter t he I EC’s/I R B’s 
a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he trial.” I n partic ular a n d i n li ne wit h res pecti ve 
re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he I nvesti gat or of A Es t hat are b ot h seri o us a n d 
u ne x pecte d a n d are c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d u ne x pecte d 
seri o us a d verse reacti o ns” or S U S A Rs). T he I n vesti gat or s h o ul d place c o pies of Safet y Re p orts i n 
t he I nvesti gat or Site File. Nati o nal re g ulati o ns wit h re gar d t o Safet y Re p ort n otificati o ns t o 
I n vesti gat ors will be ta ke n i nt o acc o u nt.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 4 9
F or trials c o vere d b y t he E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities re gar di n g 
t he re p orti n g of S A Es/ S U S A Rs/ Safet y Iss ues will be carrie d o ut i n acc or da nce wit h t hat Directi ve 
a n d wit h t he relate d Detaile d G ui da nce d oc u me nt s.
7. 4. 1. 7
M o nit ori n g of S u bjects wit h A d verse E ve nts
A d verse e ve nts are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he trial (see Secti o n 7. 4. 1. 3 ) 
a n d are assesse d f or fi nal o utc o me at t he P T D 3 6 5 v isit. All S A Es o n g oi n g at t he E O T v isit m ust 
be m o nit ore d a n d f oll o we d u p b y  the I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, 
u nless t he s u bject is d oc u me nte d as “l ost t o f oll o w-u p”. Reas o na ble atte m pts t o o btai n t his 
i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure 
t hat a n y necessar y a d diti o nal t hera pe utic meas ures a n d f oll o w- u p pr oce d ures are perf or me d. 
7. 4. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure 
O nl y  pre g na ncies c o nsi dere d b y  the I n vesti gat or t o be relate d t o trial treat me nt (e. g., res ulti n g fr o m 
a dr u g i nteracti o n wit h a c o ntrace pti ve me dicati o n) are c o nsi dere d t o be A E s. H o we ver, all 
pre g na ncies wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n 7. 4. 1. 3 m ust 
be rec or de d b y  co n ve nti o n i n t he S A E pa ge/secti o n of t he eC R F. T he sa me r ule a p plies t o 
pre g na ncies i n fe male s u bjects a n d t o pre g na ncies i n fe male part ners of male s u bjects. T he 
I n vesti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n e x pe dite d ma n ner of a n y pre g na nc y usi n g t he 
Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d acc or di n g t o t he sa me pr ocess as descri be d 
f or S A E re p orti n g i n Secti o n 7. 4. 1. 4.  
I n vesti gat ors m ust 
acti vel y foll o w u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he s u bjects are wit h dra w n fr o m t he trial.
T he I n vesti gat or m ust n otif y  t he S p o nsor/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y  Re p ort 
F or m . If a n a b n or mal o utc o me occ urs , t he S A E Re p ort F or m will be use d if t he s u bject s ustai ns 
a n e ve nt a n d t he Pare nt - C hil d/ Fet us A E Re p ort F or m if t he c hil d/fet us s ustai ns a n e ve nt.
A n y  ab n or mal o utc o me m ust be re p orte d i n a n e x pe dite d ma n ner as descri be d i n Secti o n 7. 4. 1. 4,  
w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da y s after deli ver y.
I n the e ve nt of a pre g na nc y  in a s u bject occ urri n g d uri n g t he c o urse of t he trial, t he s u bject m ust 
be disc o nti n ue d fr o m trial me dicati o n i m me diatel y. T he S p o ns or/ desi g nee m ust be n otifie d 
wit h o ut dela y  a n d t he s u bject m ust be f oll o we d as me nti o ne d a b o ve.
7. 4. 3
Cli nic al L a b or at or y Assess me nts
It is esse ntial t hat t he S p o ns or or desi g nee be pr o vi de d wit h a list of la b orat or y nor mal ra n ges 
bef ore s hi p me nt of trial dr u g. A n y c ha n ge i n la b orat or y nor mal ra n ges d uri n g t he trial will 
a d diti o nall y be f orwar de d t o t he S p o ns or or desi g nee.
Res ults m ust be a vaila ble pri or t o t he first d ose of I M P. T he re p ort of t he res ults m ust be retai ne d 
as part of t he s u bject’s me dical rec or d or s o urce d oc u me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 4 9
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he f oll o wi n g cli nical la b orat or y tests, f oll o wi n g t he 
ti mi n g n ote d i n t he Sc he d ule s of Assess me nts (Ta ble 1, Ta ble 2, Ta ble 3, Ta ble 4, Ta ble 5, Ta ble 6
a n d Ta ble 7 f or P hase Ia [ Ar m A ca ps ule c o h ort], P hase Ia [ Ar m A ta blet c o h ort], P hase I b – f irst 
3 s u bjects [Ar m A, N S C L C c o h ort], P hase I b [Ar m A, N S C L C c o h ort], P hase Ia [ Ar m B, S C C H N
c o h ort], P hase I b [Ar m B, S C C H N c o h ort] a n d a ncillar y c P o P parts , res pecti vely) . All sa m ples 
s h o ul d be clearl y i de ntifie d. Uri nal ys is (se di me nt a n d pr otei n c o nte nt) will als o be perf or me d at 
s pecifie d ti me p oi nts.
T a ble 1 5  
Re q uire d L a b or at or y S afet y Tests
S er u m C h e mi str y
H e m at ol o g y
Al b u mi n
W h it e bl o o d c ell s a n d diff er e nti al c o u nt
Al k ali n e p h o s p h at a s e
H e m o gl o bi n
Al a ni n e a mi n otr a n sf er a s e
H e m at o crit
A s p art at e a mi n otr a n sf er a s e
R e d bl o o d c ell s
Bl o o d ur e a nitr o g e n
M e a n c or p u s c ul ar v ol u m e
C al ci u m
M e a n c or p u s c ul ar h e m o gl o bi n
Cr e ati n e p h o s p h o ki n a s e
M e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n
Cr e ati ni n e
R eti c ul o c yt e s
Pl at el et c o u nt
G a m m a gl ut a m yltr a n sf er a s e
A b s ol ut e l y m p h o c yt e c o u nt 
Gl u c o s e
A b s ol ut e n e utr o p hil c o u nt 
L a ct at e d e h y dr o g e n a s e
M a g n e si u m
C o a g ul ati o n
P h o s p h or o u s
I nt er n ati o n al n or m ali z e d r ati o 
P ot a s si u m
A cti v at e d p arti al t hr o m b o pl a sti n ti m e
S o di u m
T ot al bilir u bi n
I nf e cti o n s cr e e n
T ot al pr ot ei n
H e p atiti s B
Uri c a ci d
H e p atiti s C
β- h u m a n c h ori o ni c g o n a d otr o pi n i n f e m al e s u bj e ct s (if 
a p pli c a bl e)
H u m a n i m m u n o d efi ci e n c y vir u s ( a c c or di n g t o l o c al 
pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e)
F or w o me n of c hil d beari n g p ote ntial, pre g na nc y testi n g (ser u m β -H C G) will be perf or me d d uri n g 
t he Scree ni n g Peri o d a n d at t he visits s pecifie d i n t he Sc he d ule of Assess me nts . S u bjects after 
me n o pa use (a ge-relate d a me n orr hea ≥1 2 c o nsec uti ve m o nt hs) or s u bjects w h o ha ve u n der g o ne 
h y sterect o my or bilateral o o p h orect o m y are e xe m pt fr o m pre g na nc y testi n g.
Details o n t he bl o o d v ol u me t o be dra w n fr o m eac h s u bject d uri n g t he trial are prese nte d i n a 
se parate la b orat or y d oc u me nt.
F or t he P hase Ia a n d I b parts, i ncl u di n g t he bl o o d v ol u me dra w n f or researc h p ur p oses ( P K, P D
mar kers, a n d P G x ) a n d safety assess me nts, t he t otal v ol u me of bl o o d dra w n fr o m eac h s u bject 
d uri n g t he Scree ni n g P eri o d (i ncl u di n g pre d ose) will be a p pr o xi matel y 6 1 m L . D uri n g t he 
treat me nt p eri o d, D L T peri o d a n d S h ort -ter m Safet y F oll o w -u p (e xcl u di n g pre d ose), t he t otal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 4 9
v ol u me of bl o o d dra w n fr o m eac h s u bject will be a p pr o xi matel y 1 3 8 m L
( P hase Ia, Ar m A) , 
1 8 6 m L  (first 3 s u bjects i n P hase I b, Ar m A e x pa nsi o n c o h ort [ N S C LC] ), 1 7 2 m L  (P hase I b, 
Ar m A e x pa nsi o n c o h ort [ N S C LC] ), 2 1 0 m L  (P hase Ia, Ar m B) a n d 1 8 4 m L  (P hase I b, Ar m B 
e x pa nsi o n c o h ort [ S C C H N]) . T he t otal v ol u me of bl o o d dra w n fr o m eac h s u bject i n t he a ncillar y 
c P o P part of t he trial, i ncl u di n g bl o o d sa m pli n g f or mar kers, is a p pr o xi matel y 7 3 m L .
7. 4. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
Vital si g ns ( bl o o d press ure, heart rate, a n d b o d y  te m perat ure), b o d y  wei g ht, a n d E C O G P S will be 
meas ure d as descri be d i n t he Sc he d ule of Assess me nts: (Ta ble 1,  Ta ble 3 , Ta ble 4 , Ta ble 5 , 
Ta ble 6 a n d Ta ble 7 f or P hase Ia [ Ar m A] , P hase I b – f irst 3 s u bjects [Ar m A, N S C L C c o h ort], 
P hase I b [Ar m A, N S C L C c o h ort], P hase Ia [ Ar m B, S C C H N c o h ort], P hase Ib [ Ar m B, S C C H N
c o h ort] a n d a ncillar y c P o P parts , res pecti vel y). If p ossi ble, diast olic/s y st olic bl o o d press ure s h o ul d 
be ta ke n o n t he sa me ar m at eac h visit.
P h y sical e xa mi nati o ns will be o btai ne d pre d ose a n d p ost d ose. Vital si g ns (bl o o d press ure, heart 
rate, a n d b o d y  te m perat ure) assess me nts s h o ul d be perf or me d pre d ose a n d 2 t o 3 h o urs p ost d ose .
B o d y w ei g ht will be meas ure d pre d ose o nl y. 1 2- lea d E C Gs (i n tri plicate after t he s u bject has bee n 
s u pi ne f or at least 5 mi n utes) s h o ul d be perf or me d pre d ose a n d 2 t o 3 h o urs p ost d ose o n Fracti o n 
D a y  1, a n d 2 h o urs p ost d ose o n Fracti o n Da y  1 0.
I n t he a ncillar y c P o P part of t he trial , vital si g ns a n d b o d y wei g ht s h o ul d be meas ure d pre d ose.
7. 5
P h ar m ac o k i netics
7. 5. 1
S a m ple C ollecti o n
Details of P K bl o o d sa m ple c ollecti o n a n d pr ocessi n g pr oce d ures, st ora ge, a n d tra ns p ortati o n will 
be s u m marize d i n t he la b orat or y  s pecificati o ns d oc u me nt.
F or details of P K bl o o d sa m pli n g ti me p oi nts i n t he P hase Ia, P hase I b, a n d a ncillar y c P o P parts of 
t he trial, see Ta ble 9 . 
P har mac o ki netic sa m pli n g s h o ul d be perf or me d wit hi n ± 1 5 mi n utes of t he first 3 0 mi n ute p ost d ose 
sa m ple c ollecti o ns, a n d wit hi n ± 3 0 mi n utes f or s u bse q ue nt sa m pli n g at eac h sa m pli n g d a y . T he 
pre d ose sa m ple s h o ul d be ta ke n wit hi n 1 h o ur bef ore d osi n g at eac h sa m pli n g da y. A p pr o xi matel y 
2 m L  of bl o o d s h o ul d be c ollecte d at eac h sc he d ule d ti me. T he dr u g a d mi nistrati o n, act ual date 
a n d e xact bl o o d sa m pli n g ti me m ust be rec or de d.
T he S M C ma y m o dif y  t he P K sa m pli n g sc he d ule base d u p o n P K i nf or mati o n c ollecte d d uri n g t he 
trial. T he S M C is n ot e x pecte d t o i ncrease t he o verall a m o u nt of bl o o d t o be c ollecte d f or P K 
sa m pli n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 4 9
7. 5. 2
P h ar m ac o k i netic C alc ul ati o ns
7. 5. 2. 1
N o n C o m p art me nt al A n al ysis
Ca ps ule f or m ulati o n:
T he f oll o wi n g P K para meters will be calc ulate d f or t he M 3 8 1 4
c o nce ntrati o n data o btai ne d o n 
Fracti o n D a y  1 a n d Fracti o n Da y  1 0 (if Fracti o n Da y 1 0 is o n a Fri da y, t he n t hese e val uati o ns will 
be d o ne o n Fracti o n Da y 9) i n t he P hase Ia part usi n g n o nc o m part me ntal a nal ysis a p pr oac hes as 
a p pr o priate:

C ma x

Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (tma x )

A U C o ver t he d osi n g i nter val after m ulti ple d osi n g ( A U Cτ) (Fracti o n Da y  1 0 o nl y ) 

A U C fr o m ti me zer o t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0-t) ( Fracti o n Da y 1 
o nl y ) A U C
fr o m ti me zer o e xtra p olate d t o i nfi nit y ( A U C0- ∞, Fracti o n Da y  1 a n d o nl y if 
mea ni n gf ul o n Fracti o n Da y  1 0)

A p pare nt ter mi nal half -life (t1/ 2)

Oral cleara nce ( C L/f) ( Fractio n Da y  1 o nly)

Oral cleara nce at stea d y s tate ( C Lss/f) ( Fracti o n Da y 1 0 o nly)

A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase ( Vz/f) ( Fracti o n Da y 1 o nly)

A p pare nt v ol u me of distri b uti o n at stea d y  state ( Vss/f) ( Fracti o n Da y 1 0 o nl y )

Acc u m ulati o n rati o f or A U C ( Racc[ A U C]) ( Fracti o n Da y 1 0 o nl y )

Acc u m ulati o n rati o f or C ma x ( Racc[ Cma x ]) ( Fracti o n Da y 1 0 o nl y ).
Ta blet f or m ulati o n:
T he f oll o wi n g P K para meters will be calc ulate d f or t he M 3 8 1 4
c o nce ntrati o n data o btai ne d o n 
Fracti o n Da y  1, 6 (if a patie nt d oes n ot start treat me nt o n a M o n da y, t he n “ F D 6” bec o mes t he F D 
t hat is cl osest t o a M o n da y. T heref ore, t here will be a was h-o ut of M 3 8 1 4 o ver t he wee ke n d) a n d 
Fracti o n D a y  10 (if Fracti o n D a y 1 0 is o n a Fri da y , t he n t hese e val uati o ns will be d o ne o n Fr acti o n 
D a y  9) i n t he P hase Ia part usi n g n o nc o m part me ntal a nalys is a p pr oac hes as a p pr o priate:

C ma x

Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (t ma x )

A U C o ver t he d osi n g i nter val after m ulti ple d osi n g ( A U C τ) ( Fracti o n Da y 1 0 o nl y) 

A U C fr o m ti me zer o t o the ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C0-t) ( Fracti o n Day 1 
a n d Fracti o n D a y  6) A U C fr o m ti me zer o e xtra p olate d t o i nfi nit y ( A U C0- ∞, Fracti o n Da y 1 a n d 
Fracti o n Da y  6, a n d o nl y if mea ni n gf ul o n Fracti o n Da y 1 0)

A p pare nt ter mi nal half -life (t1/ 2)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 4 9

Oral cleara nce ( C L/f) ( Fracti o n Da y  1 a n d Fracti o n Da y 6 o nl y )

Oral cleara nce at stea d y s tate ( C Lss/f) ( Fracti o n Da y 1 0 o nly)

A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase ( Vz/f) ( Fracti o n Da y  1 a n d Fracti o n 
D a y 6 o nl y )

A p pare nt v ol u me of distri b uti o n at stea d y  state ( Vss/f) ( Fracti o n Da y 1 0 o nl y)

Acc u m ulati o n rati o f or A U C ( R acc[ A U C]) ( Fracti o n Da y 1 0 o nl y)

Acc u m ulati o n rati o f or C ma x ( Racc[ Cma x ]) ( Fracti o n Da y 1 0 o nl y).
A d diti o nal P K para meters ma y  be calc ulate d.
Plas ma c o nce ntrati o n of M 3 8 1 4
will be deter mi ne d b y  a Li q ui d c hr o mat o gra p h y- ta n de m mass 
s pectr o metr y met h o d .
7. 5. 2. 2
P o p ul ati o n P K A n al ysis a n d Si m ul ati o n
P o p ul ati o n p h ar m ac o ki netic
O bjecti ves of t he p o p ulati o n P K a nal y sis will be:

I de ntificati o n of p o p ulati o n P K m o del of M 3 8 1 4

Esti mati o n of t y pical p o p ulati o n P K para meters of M 3 8 1 4
as cleara nces, ce ntral a n d peri p heral 
v ol u mes, etc.

Esti mati o n of t he varia bilit y  of t he p o p ulati o n P K para meters

I de ntificati o n of a d diti o nal c o variates, s uc h as de m o gra p hics, c o me dicati o n or me dical hist or y, 
t hat are si g nifica nt pre dict ors of P K varia bilit y , R T d ose .
Si m ul ati o n
If re q ueste d, si m ulati o n of a n alter nati ve d osi n g re gi me n will be perf or me d i n or der t o ac hie ve a 
certai n tar get.
T he p o p ulati o n a nal ysis will be c o n d ucte d wit h s oft ware pac ka ge N O N M E M ( versi o n 7. 2. 0), 
w hile t he si m ulati o ns will be perf or me d wit h eit her N O N M E M or SI M U L X s oft ware.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 4 9
7. 7
Ot her A ssess me nts
N ot a p plica ble.
8
St atistics
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 4 9
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 4 9
8. 2
R a n d o miz ati o n
N ot a p plica ble .
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nts
T he p ri mar y e n d p oi nts f or t he trial are:

P hase Ia ( Ar m A): Occ urre nce of D L T u p t o 5 wee ks after first d ose of M 3 8 1 4
i n c o m bi nati o n 
wit h palliati ve fracti o nate d R T

P hase Ia ( Ar m B): Occ urre nce of D L T u p t o 1 2 wee ks after first d ose of M 3 8 1 4
i n c o m bi nati o n 
wit h sta n dar d C R T ( wit h cis plati n) wit h c urati ve i nte nt

P hase I b ( Ar m A) – first 3 s u bjects: Occ urre nce of D L T u p t o 1 2 wee ks after t he first d ose of 
M 3 8 1 4 i n c o m bi nati o n wit h c urati vel y i nte n de d fracti o nate d R T

P hase I b: Safet y a n d t olera bilit y as f oll o ws:
o
Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 4 9
o
Res ults of la b orat or y tests, vital si g ns, E C Gs.
8. 3. 2
Sec o n d ar y E n d p oi nts
8. 3. 2. 1
S afet y E n d p oi nts

Occ urre nce of T E A Es (se verit y gra de d acc or di n g t o t he N CI  C T C A E v 4. 0 3)

Res ults of la b orat or y tests, vital si g ns, E C Gs .
8. 3. 2. 2
Effic ac y E n d p oi nts

Best o verall res p o nse base d o n t u m or e val uati o ns ma de b y  In vesti gat or i n acc or da nce wit h 
R E CI S T v 1. 1

T u m or size meas ure me nt base d o n I n vesti gat or assess me nt i n acc or da nce wit h R E CI S T v 1. 1

P F S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o pr o gressi ve disease ( per 
R E CI S T v 1. 1) base d o n t he I nvesti gat or assess me nt or deat h fr o m a n y ca use, a n d l ocal/l ocal 
re gi o nal t u m or c o ntr ol ( P hase I b, Ar m B e x pa nsi o n c o h ort)

O S ti me defi ne d as ti me fr o m t he first d ose of trial treat me nt t o t he date of deat h fr o m a n y c a use 
8. 3. 2. 3 
P h ar m ac o k i netic E n d p oi nts
Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part (ca ps ule): 

Fracti o n Da y  1 – Cma x , tma x , A U C 0-t, A U C 0 - ∞, t1/ 2, C L /f, Vz/f

Fracti o n Da y  1 0 – Cma x , tma x , A U C τ, A U C0- ∞, t1/ 2, C L ss/f, Vss/f , Racc[ A U C], Racc[ Cma x ].
Plas ma P K para meters of M 3 8 1 4
f or P hase Ia part (ta blet): 

Fracti o n Da y  1 – Cma x , tma x , A U C0 -t, A U C0- ∞, t1/ 2, C L/f, Vz/f

Fracti o n Da y  6 – Cma x , tma x , A U C0-t, A U C0- ∞, t1/ 2, C L/f, Vz/f

Fracti o n Da y  1 0 – C ma x , tma x , A U Cτ, A U C 0- ∞, t1/ 2, C Lss/f, Vss/f, Racc[ A U C], Racc[ Cma x ].
P o p ulati o n P K para meters f or P hase I b a n d t he a ncillar y c P o P part of t he trial will be re p orte d i n 
a se parate P K re p ort, w hic h will n ot be part of t he Cli nical Trial Re p ort f or t his trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 4 9
8. 4
A n al ysis Sets
All S u bjects A n al ysis Set
T he All s u bjects (A L L ) a nal ys is set will i ncl u de all t he s u bjects w h o ha ve si g ne d t he I CFs (i.e.,
scree ni n g fail ures pl us s u bjects e nr olle d). T he A L L a nal ys is set will be use d t o s u m marize a n d 
descri be t he s u bject dis p ositi o n, a n d deat hs, u nless o t her wise state d.
F ull A n al ysis Set/ S afet y A n al ysis Set
T he F ull A nal y sis Set ( F A S)/Safet y ( S A F) a nal ysis set will i ncl u de all s u bjects w h o recei ve at 
least o ne a d mi nistrati o n of t he trial me dicati o n. T he F A S/ S A F a nal ys is set will be use d f or all 
baseli ne , safet y (e xce pt f or D L Ts a n d deat hs), a n d efficac y s u m maries, u nless ot her wise state d.
D ose Esc al ati o n A n al ysis Set
T he D ose Escalati o n ( D E) a nal ys is set will i ncl u de all s u bjects treate d i n d ose escalati o n c o h orts 
w h o recei ve at least 8 0 % of M 3 8 1 4
a n d R T pla n ne d d ose a n d c o m plete t he D LT peri o d (t hr o u g h 
5 wee ks [P hase Ia, Ar m A] or 1 2 wee ks [ P hase Ia, Ar m B a n d P hase I b, first 3 s u bjects i n t he 
e x pa nsi o n c o h ort of Ar m A - N S C L C] after start of M 3 8 1 4 treat me nt). T he D E set will als o i ncl u de 
s u bjects treate d i n d ose escalati o n c o h orts w h o e x perie nce a D L T d uri n g t he D L T peri o d re gar dless 
of t he recei ve d a m o u nt of eac h dr u g. T he D E a nal ysis set will be use d f or t he D L T s u m maries. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 4 9
P h ar m ac o ki netics A n al ysis Set
T he P K e val uati o n ( P K) a nal ys is set i n P hase Ia a n d P hase I b parts will i ncl u de s u bjects w h o ha ve 
recei ved at least t he first d ose of t he dr u g a n d pr o vi de d P K sa m ples as per pr ot oc ol f or at least 
6 h o urs f oll o wi n g first d osi n g o n Fracti o n D a y  1.
8. 5
Descri pti o n of St atistic al A n al yses
8. 5. 1
Ge ner al C o nsi der ati o ns
All a nal yses will be pre pare d b y  f or m ulati o n (ca ps ule, ta blet) a n d d ose le vel (if a p plica ble), a n d 
will be descri be d i n detail i n t he Statistical A nal y sis Pla n ( S A P). 
T he f oll o wi n g s u m mar y statistics will be use d t o s u m marize t he trial data per d ose le vel u nless 
ot her wise s pecifie d:

C o nti n u o us varia bles: n u m ber of n o n missi n g o bser vati o ns, mea n, sta n dar d de viati o n ( S D), 
me dia n, mi ni m u m, a n d ma xi m u m, 9 5 % CI s f or t he mea n, as a p pr o priate

Cate g o rical varia bles: fre q ue ncies a n d perce nta ges.
T he c ut off f or d ose escalati o n assess me nts b y  the S M C i n P hase Ia will be tri g gere d b y  th e 
c o m pleti o n of t he D L T peri o d of t he last s u bject i n t he res pecti ve c o h ort.
T he c ut off f or a nal ys is of t he sec o n dar y safet y data fr o m t he P hase Ia d ose escalati o n a n d M T D 
deter mi nati o n p hase of t he trial will be tri g gere d w he n t he last s u bject e nr olle d reac hes t he sec o n d 
p ost -treat me nt t u m or assess me nt or e x perie nces deat h or pre mat ure wit h dra wal f or a n y reas o n, 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 4 9
w hic he ver c o mes first. T he c ut off f or t he c P o P a nal ysis will be tri g gere d w he n t he last s u bject 
e nr olle d i n t he a ncillar y c P o P part of t he trial c o m pletes t he assess me nt at t he E O T visit. 
T he c ut off f or t he a nal ys is of t he safety a n d efficac y e n d p oi nts i n t he P hase I b e x pa nsi o n c o h ort s
(i ncl u di n g t he first 3 N S C L C s u bjects treate d at a l o wer d ose) will be tri g gere d b y  t he date w he n 
t he last e nr olle d s u bject reac hes t he sec o n d p ost -treat me nt t u m or assess me nt or e x perie nces deat h 
or pre mat ure wit h dra wal f or a n y rea s o n, w hic he ver c o mes first.
F ull details of t he pla n ne d a nal ys es will be descri be d i n t he trial S A P se paratel y for t he d ose 
escalati o n a n d t he e x pa nsi o n part of t he trial.
8. 5. 2
A n al ysis of Pri m ar y E n d p oi nts
P hase Ia a n d t he first 3 s u bjects i n P hase I b (Ar m A) : T he n u m ber a n d pr o p orti o n of s u bjects 
e x perie nci n g a D L T will be re p orte d se parately f o r eac h ar m a n d f or m ulati o n b y  d ose le vel, base d 
o n t he o bser vati o n of D L Ts u p t o 5 wee ks ( P hase Ia, Ar m A) or 1 2 wee k s (P hase Ia, Ar m B a n d 
first 3 s u bjects i n P hase I b [ Ar m A] ) after t he first d ose of M 3 8 1 4 ta ki n g i nt o acc o u nt t he k n o w n 
t o xicities wit h R T al o ne. P osteri or pr o ba bilities ( 2. 5 %, 2 5 %, 5 0 %, 7 5 % a n d 9 7. 5 % q ua n tiles) after 
t he last c o h ort will be esti mate d (if a p plica ble). T he D E a nal ys is set will be use d f o r t his a nalys is.
8. 5. 3
A n al ysis of Sec o n d ar y E n d p oi nts
8. 5. 3. 1 
P h ar m ac o k i netics
8. 5. 3. 1. 1
Descri pti ve St atistics
T he P K varia bles will be a nal yze d descri pti vel y  for eac h treat me nt se parately.  Descri pti ve 
statistics i ncl u de N, arit h metic mea n, ge o metric mea n, S D, sta n dar d err or of t he mea n, me dia n, 
mi ni m u m, ma xi m u m, c oefficie nt of variati o n ( %), a n d ge o metric c oefficie nt of variati o n . T he dr u g 
c o nce ntrati o n i n plas ma at eac h sa m pli n g ti me will be prese nte d o n t he ori gi nal scale f or all 
s u bjects w h o partici pate i n t he trial a n d pr o vi de at least 1 plas ma c o nce ntrati o n of M 3 8 1 4 . Val ues 
bel o w t he l o wer li mit of q ua ntificati o n will be ta ke n as zer o f or descri pti ve statistics of 
c o nce ntrati o ns. 
I n di vi d ual plas ma c o nce ntrati o n-ti me pr ofiles (li near a n d se mi-l o garit h mic scale) will be pl otte d 
b y  treat me nt. Mea n plas ma c o nce ntrati o ns per treat me nt will be pl otte d wit h S D b y  sc he d ule d ti me 
p oi nts. If e vi de nce is o btai ne d t hat wei g ht affects t he P K pa ra meters, t he n a nal yses will als o be 
perf or me d f or wei g ht -n or malize d P K para meters. F or mal statistical h y p ot heses are n ot set u p. All 
statistical tests will be perf or me d i n a n e x pl orat or y ma n ner. All a nal yses will be base d o n t he P K 
a nal ys is set. 
Details of t he statistical a nal y ses will be descri be d i n t he S A P. 
8. 5. 3. 1. 2
A n al ysis of D ose Pr o p orti o n alit y
Details of t he statistical a nal y ses will be descri be d i n t he S A P.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 4 9
8. 5. 3. 3
Effic ac y A n al yses
S u m mar y  statistics as descri be d i n Secti o n 8. 5. 1 will be use d f or t he s u m mar y of efficac y en d p oi nts 
b y  dose le vel a n d c o h ort. Pr o gressi o n free s ur vi val a n d O S will be calc ulate d f or t he e x pa nsi o n 
c o h ort o nl y. 
8. 5. 4
A n al ysis of S afet y a n d Ot her E n d p oi nts
8. 5. 4. 1
A d verse E ve nts
A d verse E ve nts will be c o de d acc or di n g t o t he latest a vaila ble versi o n of t he Me dical Dicti o nar y  
f or Re g ulat or y  Acti vities ( Me d D R A). Se verit y  of A Es will be gra de d usi n g t he C T C A E (v 4. 0 3) 
t o xicit y gra des. A d verse e ve nts relate d t o trial me dicati o n will be defi ne d as a n y A E c o nsi dere d 
relate d t o M 3 8 1 4 . I n a d diti o n, missi n g classificati o ns c o ncer ni n g trial me dicati o n relati o ns hi ps 
will be c o nsi dere d relate d t o t he trial dr u g. 
T he i nc i de nce a n d ty pe of t he f oll o wi n g T E A Es o bser ve d u ntil 3 0 da ys fr o m e n d of treat me nt will 
be a nal yz e d re p orti n g se paratel y t h ose relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n: 

T E A Es of a n y gra de a n d S A Es

T E A Es a n d S A Es of a n y gra de relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n

T E A Es wit h C T C A E Gra de ≥3

T E A Es relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n wit h C T C A E Gra de ≥3

A Es lea di n g t o wit h dra wal, d ose m o dificati o ns or per ma ne nt t rial treat me nt disc o nti n uati o n

A Es relate d t o M 3 8 1 4 , R T , C R T or t heir c o m bi nati o n lea di n g t o wit h dra wal, d ose m o dificati o ns 
or per ma ne nt t rial treat me nt disc o nti n uati o n

A Es lea di n g t o deat h

A Es relate d t o M 3 8 1 4 , R T, C R T or t heir c o m bi nati o n lea di n g t o deat h.
T hese will be s u m marize d acc or di n g t o Me d D R A S y ste m Or ga n Classes an d Preferre d Ter ms. 
S u bject s w h o ter mi nate treat me nt will be dis pla ye d i n a b y -s u bject listi n g, a n d s u m marize d b y 
pri mar y  wit h dra wal reas o n f or eac h treat me nt gr o u p. 
All re p orte d deat hs d uri n g t hera p y a n d deat hs wit hi n 3 0 d a y s after first a n d last d ose of trial 
treat me nt as well as reas o ns f or deat h will be ta b ulate d (f or all s u bjects e nr olle d). Deat hs wit hi n 
3 0 da y s fr o m last d ose a d mi nistrati o n a n d reas o ns f or t he m will als o be ta b ulate d. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 4 9
8. 5. 4. 2
L a b or at or y V ari a bles
La b orat or y  res ults will be classi fie d b y  gra de acc or di n g t o t he C T C A E v 4. 0 3. T he w orst o n- trial 
gra des after t he first d ose of trial treat me nt will be s u m marize d.
S hifts i n t o xicit y gra des fr o m first treat me nt t o hi g hest gra de will be dis pla y e d. Res ults f or 
varia bles t hat are n ot part of N CI -C T C A E ( v 4. 0 3) will be prese nte d as bel o w, wit hi n, or a b o ve 
n or mal li mits. O nl y  su bjects wit h p ost baseli ne la b orat or y val ues will be i ncl u de d i n t hese a nal ys es. 
8. 5. 4. 3
P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n, i ncl u di n g vital si g ns ( b o dy t e m perat ure, heart rate, a n d bl o o d press ure), a n d 
1 2- lea d E C G rec or de d at baseli ne a n d after a d mi nistrati o n of M 3 8 1 4
will be prese nte d. Eac h E C G 
para meter will be s u m marize d b y  descri pti ve statistics per time p oi nt, a n d c ha n ges fr o m baseli ne 
will be calc ulate d. A cate g orical a nal ys is will be perf or me d f or Q Tc F data. Data will be f urt her 
a nal yz e d usi n g c o nce ntrati o n effect m o deli n g f or baseli ne -c orrecte d Q Tc F val ues o btai ne d at 
D a y 1. 
8. 6
I nteri m A n al ysi s
N o f or mal i nteri m a nal yses are pla n ne d . H o we ver , a d mi nistrati ve l o o ks i nt o t he data ma y
be 
perf or me d.
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he I n vesti g at or
T he I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he trial t o e ns ure t hat t he trial is perf or me d i n 
acc or da nce wit h t his pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of Helsi n ki, I CH 
G C P , a n d a n y ot her a p plica ble re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat o nl y  su bjects w h o 
ha ve gi ve n i nf or me d c o nse nt are i ncl u de d i n t he trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 4 9
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or trials c o n d ucte d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n f or mar keti n g a p pr o val a n d c o ul d c o ntri b ute si g nifica ntl y  t o t he de m o nstrati o n of 
efficac y an d safet y of a n I MP ( w hic h are c o nsi dere d “c o vere d cli nical trials” b y  the F D A), t he 
I n vesti gat or a n d all s u bIn vesti gat ors are o bli ge d t o discl ose a n y f i na ncial i nterest w hic h t he y, t heir 
s p o uses or t heir de pe n de nt c hil dren m a y  ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der st u d y. 
T his i nf or mati o n is re q uire d d uri n g t he trial a n d f or 1 2 m o nt hs f oll o wi n g c o m pleti o n of t he trial.
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or eac h s u bject pri or t o partici pati o n i n t he trial is writte n i nf or me d 
c o nse nt , w hic h m ust be gi ve n bef ore a n y trial-relate d acti vities are carrie d o ut. A de q uate 
i nf or mati o n m ust t heref ore be gi ve n t o t he s u bject b y  the I n vesti gat or or a n a p pr o priate desi g nee 
(if l ocal re g ulati o ns per mit) bef ore i nf or me d c o nse nt is o btai ne d. 
A s u bject i nf or mati o n s heet m ust be pre pare d i n t he l ocal la n g ua ge i n acc or da nce wit h I CH G C P
a n d will be pr o vi de d b y t he S p o ns or f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt. I n a d diti o n t o 
pr o vi di n g t his writte n i nf or mati o n t o a p ote ntial s u bject, t he I n vesti gat or or a desi g nate will i nf or m 
t he s u bject ver ball y of all perti ne nt as pects of t he trial, usi n g la n g ua ge c h ose n s o t hat t he 
i nf or mati o n ca n be f ull y a n d rea dil y un derst o o d b y  la ypers o ns. T he s u bject will be gi ve n s ufficie nt 
ti me t o rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal 
i nf or mati o n a n d clarificati o n.
If per mitte d b y nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y  inf or m t he s u bject 
a b o ut t he trial a n d si g n t he I CF, as a b o ve.
After t he i nf or mati o n is pr o vi de d b y  the I n vesti gat or, t he IC F m ust be si g ne d a n d date d b y  the 
s u bject a n d t he I n vesti gat or. 
T he si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he I n vesti gat or’s site, a n d 
m ust be safel y arc hi ve d s o t hat t he f or ms ca n be retrie ve d at a n y t i me f or m o nit ori n g, a u diti n g a n d 
i ns pecti o n p ur p oses. A c o p y of t he si g ne d a n d date d i nf or mati o n a n d IC F s h o ul d be pr o vi de d t o 
t he s u bject pri or t o partici pati o n.
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o i nf or me d c o nse nt, 
t he I nvesti gat or will re vise t he s u bject i nf or mati o n s heet a n d a n y ot her writte n i nf or mati o n t o be
pr o vi de d t o t he s u bjects a n d s u b mit t he m t o t he I E C/I RB f or re vie w a n d o pi ni o n. Usi n g t he 
a p pr o ve d re vise d s u bject i nf or mati o n s heet a n d ot her writte n i nf or mati o n, T he I nvesti gat or will 
e x plai n t he c ha n ges t o t he pre vi o us versi o n t o eac h trial s u bject a n d o btai n ne w writte n c o nse nt f or 
c o nti n ue d partici pati o n i n t he trial. T he s u bject wi ll be gi ve n s ufficie nt ti me t o rea d t he i nf or mati o n 
a n d t he o p p ort u nit y  t o as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d clarificati o n a b o ut 
t he c ha n ges.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 4 9
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n , i m me diatel y after i nf or me d 
c o nse nt has bee n o btai ne d. T his n u m ber will ser ve as t he s u bject’s i de ntifier i n t he trial as well as 
i n t he cli nical trial data base.
All s u bject data c ollecte d i n t he trial will be st ore d u n der t h e a p pr o priate s u b ject n u m ber. O nl y t he 
I n vesti gat or will be a ble t o li n k trial data t o a n i n di vi d ual s u bject via a n i de ntificati o n list ke pt at 
t he site. F or eac h s u bject, ori gi nal me dical data will be accessi ble f or t he p ur p oses of s o urce data 
verificati o n b y  the M o nit or,
a u dits a n d re g ulat or y ins pecti o ns, b ut s u bject c o nfi de ntialit y will be 
strictl y mai ntai ne d.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g s u bject data. S u bjects will be i nf or me d acc or di n gl y, a n d will be re q ueste d t o gi ve t heir 
c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns.
Bl o o d a n d t u m or tiss ue sa m ples f or P G x a n d bi o mar kers will be st ore d f or u p t o 1 2 ye ars after trial 
c o m pleti o n. D uri n g t his ti me, t he sa m ples m a y be rea nal yz e d f or ne wl y i de ntifie d mar kers or wit h
n e w or i m pr o ve d tec h n ol o gy . After 1 2 ye ars, t he sa m ples will be destr o ye d or f ull y an o n y mize d 
or a ne w I E C/I R B a p pr o val a n d i nf or me d c o nse nt will be re q ueste d t o kee p t he sa m ples f or a n 
a d diti o nal peri o d. If t u m or tiss ue re mai ns, t he site will be n otifie d a n d t he t u m or tiss ue will be 
ret ur ne d t o t he site u p o n re q uest. If t he site d oes n ot re q uest t he ret ur n of t he t u m or tiss ue, it will 
be destr o ye d.
9. 4
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d
S u bjects e nr olle d i n t his cli nical trial will be pr o vi de d wit h E mer ge nc y  Me dical S u p p ort car ds 
d uri n g t heir trial partici pati o n, w hic h will be f ur nis he d b y  the S p o ns or. T he E mer ge nc y  Me dical 
S u p p ort car d is base d o n t he nee d t o pr o vi de cli nical trial s u bjects wit h a wa y  of i de ntif yi n g 
t he msel ves as partici pati n g i n a cli nical trial, a n d s u bse q ue ntl y to gi ve healt h care pr o vi ders access 
t o t he i nf or mati o n a b o ut t his partici pati o n t hat ma y  be nee de d t o deter mi ne t he c o urse of t he 
s u bject’s me dical treat me nt.
T his ser vice is desi g ne d t o pr o vi de i nf or mati o n t o healt h care pr o vi ders w h o are n ot part of t he 
cli nical trial; a n d t his ma y i ncl u de t he p ossi bilit y  of e mer ge nc y un bli n di n g if nee de d, i n case of 
bli n de d trials.
Cli nical trial In vesti gat ors, w h o are alrea d y a ware of t he cli nical trial pr ot oc ol a n d treat me nt, ha ve 
ot her mea ns of accessi n g t he necessar y  me dical i nf or mati o n f or t he ma na ge me nt of e mer ge ncies 
occ urri n g i n t heir s u bjects.
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n vesti gat or cari n g f or t he 
affecte d s u bject. T he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact i nf or mati o n o n 
t he car d f or t his p ur p ose. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y s ubse q ue nt acti o n will 
f oll o w t he sta n dar d pr ocess esta blis he d f or 
I n vesti gat ors.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 4 9
I n cases w here t he I n vesti gat or is n ot a vaila ble, Merc k 
Ser o n o/ E M D Ser o n o pr o vi des t he 
a p pr o priate mea ns t o c o ntact a S p o ns or p h y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o u r c o ntact 
n u m ber at a call ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate 
S p o ns or p h y sicia n t o assist wit h t he me dical e mer ge nc y.
9. 5
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects
I ns ura nce c o vera ge wi ll be pr o vi de d for eac h c o u ntr y partici pati n g t o t he trial. I ns ura nce c o n diti o ns 
s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t his cli nical trial pr ot oc ol wil l be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts (e. g., IC F s) t o t he res p o nsi ble IE C or I RB f or its fa v ora ble 
o pi ni o n or a p pr o val , w hic h will be file d i n t he I nvesti gat or Site File . A c o p y will be file d i n t he
Trial Master File .
T he I E C or I RB will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n
or a p pr o val was gi ve n a n d t he me m bers a n d v oti n g me m bers prese nt. Writte n 
e vi de nce of 
fa v ora ble o pi ni o n or a p pr o val t hat clearl y i de ntifies t he trial, t he cli nical trial p r ot oc ol versi o n a n d 
t he S u bject I nf or mati o n a n d IC F versi o n re vie we d s h o ul d be pr o vi de d. W here p ossi ble, c o pies of 
t he meeti n g mi n utes s h o ul d be o btai ne d.
A me n d me nts t o t his cli nical trial pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d I E C or I R B, 
bef ore i m ple me ntati o n of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ). Rele va nt safety i nf or mati o n will 
be s u b mitte d t o t he I EC
or I RB d uri n g t he c o urse of t he trial i n acc or da nce wit h nati o nal 
re g ulati o ns a n d re q uire me nts.
9. 7
He alt h A ut h orities
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (f or e xa m ple, I M P D ossier, S u bject 
I nf or mati o n a n d IC F ) will be s u b mitte d or n otifie d t o t he Healt h A ut h orities i n acc or da nce wit h 
all l ocal a n d nati o nal re g ulati o ns f or eac h site.
1 0
Tri al M a n a ge me nt
1 0. 1
C ase Re p ort F or m H a n dli n g
Refer t o t he Ma n ual of o perati o ns f or e C R F ha n dli n g g ui deli nes.
T he mai n p ur p ose of the e C R F is t o o btai n data re q uire d b y  the cli nical trial pr ot oc ol i n a c o m plete, 
acc urate, le gi ble a n d ti mel y. T he data i n t he e C R F s h o ul d be c o nsiste nt wit h t he rele va nt s o urce 
d oc u me nts.
T he I n vesti gat or or desi g nee is res p o nsi ble f or e ns uri n g t hat t he d ata c ollecte d i n t he c o urse of t his 
trial is acc urate a n d d oc u me nte d a p pr o priatel y o n all a p plica ble f or ms. T he y  will t he n be 
pr ocesse d, e val uate d, a n d st ore d i n a n o n ym o us f or m i n acc or da nce wit h a p plica ble data pr otecti o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 4 9
re g ulati o ns. T he I n vesti gat or m us t e ns ure t hat t he e C R Fs a n d a n y ot her ass ociate d d oc u me nts 
f or war de d t o S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a n y s u bject na mes.
T he data will be e ntere d i nt o a vali date d data base. T he C R Os Data Ma na ge me nt will be res p o nsi ble 
f or dat a pr ocessi n g, i n acc or da nce wit h t he C R Os sta n dar d o perati n g pr oce d ures . Data base l oc k 
will occ ur o nce q ualit y  co ntr ol pr oce d ure, a n d q ualit y  ass ura nce pr oce d ures (if a p plica ble) ha ve 
bee n c o m plete d. P D F files of t he e C R Fs will be pr o vi de d t o t he I n vesti ga t ors at t he c o m pleti o n of 
t he trial.
1 0. 2
S o urce D at a a n d S u bject Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y s u bject i n t he trial. It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g this s u bject file. 
T his file will c o ntai n t he de m o gra p hic a n d me dical i nf or mati o n f or t he s u bject liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 

S u bject’s f ull na me, d ate of birt h, se x, h ei g ht, wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he trial)

Trial i de ntificati o n , t hat is, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d s u bject n u m ber

Date s f or e ntr y i nt o t he trial (i nf or me d c o nse nt) a n d visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t his cli nical trial pr ot oc ol

All A E s

Date t hat t he s u bject left t he trial i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he trial or 
I M P (if a p plica ble).
A ll d oc u me nts c o ntai ni n g s o urce data m ust be file d, i nclu di n g C T or M RI  sca n i ma ges, E C G 
rec or di n gs, a n d la b orat or y res ults. S uc h d oc u me nts m ust bear t he s u bject n u m ber a n d t he date of
t he pr oce d ure. If p ossi ble, t his inf or mati o n s h o ul d be pri nte d b y  the i nstr u me nt use d t o perf or m 
t he assess me nt or meas ure me nt. As nec essar y, medical e val uati o n of s uc h rec or ds s h o ul d be 
perf or me d; all e val uati o ns s h o ul d be d oc u me nte d , si g ne d, a n d date d b y t he I n vesti gat or.
Electr o nic s u bject files will be pri nte d w he ne ver t he M o nit or perf or ms s o urce data verificati o n. 
Pri nt o uts m ust be si g ne d a n d date d b y  t he I n vesti gat or, c o u ntersi g ne d b y  t he M o nit or a n d ke pt i n 
a safe place at t he site.
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
U p o n i nitiati o n of t he trial, the I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File 
c o ntai ni n g all necessar y  trial d oc u me nts , w hic h will be c o m plete d t hr o u g h o ut t he trial a n d u p date d 
as necessar y. T he file m ust be a vaila ble f or re vie w b y  t he M o nit or, d uri n g S p o ns or a u dit s a n d f or 
i ns pecti o n b y Healt h A ut h orities d uri n g a n d after t he trial, a n d m ust be safel y arc hi ve d f or at least 
1 5 ye ars ( or l o n ger, per l ocal re q uire me nts or as ot her wise n otifie d b y  the S p o ns or) after t he e n d 
of t he trial. T he d oc u me nts t o be arc hi ve d i ncl u de t he S u bject I de ntificati o n Li st a n d t he si g ne d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 4 9
s u bject IC F s. If arc hi vi n g of the I n vesti gat or Site File is n o l o n ger p ossi ble at t he site, t he 
I n vesti gat or m ust n otif y t he S p o ns or/ desi g nee.
All ori gi nal s u bject files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble re g ulati o ns, a n d/ or as per I CH 
G C P g ui deli nes, w hic he ver is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
1 0. 4
M o nit ori n g, 
Q u ali t y Ass ur a nce a n d I ns pecti o n b y He alt h 
A ut h orities
T his trial will be m o nit ore d i n acc or da nce wit h t he I C H G C P, a n d a n y ot her a p plica ble re g ulati o ns. 
T he site m o nit or will perf or m visits t o t he trial site at re g ular i nter vals.
T he cli nical trial pr ot oc ol, eac h ste p of t he data ca pt ure pr oce d ure, a n d t he ha n dli n g of t he data, 
i ncl u di n g t he fi nal cli nical trial re p ort, will be s u bject t o i n de pe n de nt Q ualit y Ass ura nce acti vities. 
A u dits ma y  be c o n d ucte d at a n y t i me d uri n g or after t he trial t o e ns ure t he vali di t y a n d i nte grit y of 
t he trial data. Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m t he S p o ns or or a desi g nate d 
or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d t o access all trial d oc u me nts a n d 
ot her materials at t he site, i ncl u di n g t he In vesti gat or Site File, t he c o m plete d eC R Fs, all I MP a n d
I M P acc o u nta bilit y rec or ds, a n d t he ori gi nal me dical rec or ds or files f or eac h s u bject.
1 0. 5
C h a n ges t o t he Cli nic al Tri al Pr ot oc ol
C ha n ges t o t he cli nical trial pr ot oc ol will be d oc u me nte d i n writte n pr ot oc ol a me n d me nts. 
S u bsta nti ve a me n d me nts will us uall y  re q uire s u b missi o n t o t he Healt h A ut h orities a n d t o t he 
rele va nt I E C/I R B f or a p pr o val or fa v ora ble o pi ni o n. I n suc h cases, t he a me n d me nt will be 
i m ple me nte d o nl y after a p pr o val or fa v ora ble o pi ni o n has bee n o btai ne d.
Mi n or ( n o ns u bsta ntial) pr ot oc ol a me n d me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y  
t he S p o ns or a n d at t he site. T he y  will be s u b mitte d t o t he rele va nt I E C/IR B or t o Healt h A ut h orities 
o nl y  w here re q ueste d by perti ne nt re g ulati o ns. 
A n y  ame n d me nt t hat c o ul d affect t he s u bject’s a gree me nt t o partici pate i n t he trial re q uires
a d diti o nal i nf or me d c o nse nt pri or t o i m ple me ntati o n f oll o wi n g t he pr ocess as descri be d i n
Secti o n 9. 2.
1 0. 6
Cli nic al Tri al Re p ort a n d P u blic ati o n P olic y
1 0. 6. 1
Cli nic al Tri al Re p ort
After c o m pleti o n of t he trial, a cli nical trial re p ort will be writte n b y  the S p o ns or i n c o ns ultati o n 
wit h t he C o or di nati n g I nvesti gat or f oll o wi n g t he g ui da nce i n I C H T o pic E 3 Str uct ure a n d C o nte nt 
of Cli nical St u d y  Re p orts ( 1 9 9 6).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 4 9
1 0. 6. 2 
P u blic ati o n
T he first p u blicati o n will i ncl u de t he res ults of t he a nal ysis of t he pri mar y  en d p oi nts a n d will 
i ncl u de data fr o m all trial sites.
T h e I n vesti gat or will i nf or m t he S p o ns or i n a d va nce a b o ut a n y pla ns t o p u blis h or prese nt data 
fr o m t he trial. A n y p u blicati o ns a n d prese ntati o ns of t he res ults (a bstracts i n j o ur nals or 
ne ws pa pers, oral prese ntati o ns, etc.), eit her i n w h ole or i n part, b y  In vesti gat ors or t heir 
re prese ntati ves will re q uire re vie w by t he S p o ns or bef ore s u b missi o n .
T he S p o ns or will n ot s u p press p u blicati o n, b ut mai ntai ns t he ri g ht t o dela y  p u blicati o n i n or der t o 
pr otect i ntellect ual pr o pert y  ri g hts.
P osti n g of data o n E u dra C T a n d Cli n icalTrials. g o v is pla n ne d a n d will occ ur 1 2 m o nt hs after t he 
last cli nic visit of t he fi nal trial s u bject or a n ot her a p pr o priate date t o meet a p plica ble re q uire me nts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 4 9
1 1
Refere nces Cite d i n t he Te xt
1.
F o n g P C, B oss D S, Ya p T A, et al. I nhi biti o n of p ol y ( A D P-ri b ose) p oly m erase i n t u m ors fr o m 
B R C A m utati o n carriers. N E n gl J
Me d 2 0 0 9; 3 6 1( 2): 1 2 3 - 3 4.
2.
Far mer H, Mc Ca be N, L or d CJ, et al. Tar geti n g t he D N A re pair defect i n B R C A m uta nt cells 
as a t hera pe utic strate g y. Nat ure 2 0 0 5; 4 3 4( 7 0 3 5): 9 1 7- 2 1.
3.
A u de h M W, Car mic hael J, Pe ns o n R T, et al. Oral p ol y ( A D P-ri b ose) p ol y merase i n hi bit or 
ola pari b i n patie nts wit h B R C A 1 or B R C A 2 m utati o ns a n d rec urre nt o varia n ca ncer: a 
pr o of - of-c o nce pt trial. La ncet 2 0 1 0; 3 7 6( 9 7 3 7): 2 4 5- 5 1.
4.
S ha h B A, 
Q ures hi 
M M, 
L o g ue J M, et al. Assessi n g 
c u m ulati ve ac ute t o xicit y of 
c he m ora di ot hera p y i n hea d a n d nec k ca ncer wit h or wit h o ut i n d ucti o n c he m ot hera p y. A m J 
Ot olar y n g ol. 2 0 1 7; 3 8( 4): 4 5 6 - 6 1.
5.
I q bal M S, C ha w C, K o vari k J, et al. Pri mar y  co nc urre nt c he m ora diati o n i n hea d a n d nec k 
ca ncers wit h wee kl y cis plati n c he m ot hera p y:  a nal ysis of c o m plia nce, t o xicit y a n d s ur vi val. I nt 
Arc h Ot or hi n olar y n g ol. 2 0 1 7; 2 1( 2): 1 7 1- 7.
6.
H o m ma A, I na m ura N, Ori date N, et al. C o nc o mita nt wee kl y  cis plati n a n d ra di ot hera py f or 
hea d a n d nec k ca ncer. J p n J Cli n O n c ol. 20 1 1; 4 1( 8): 9 8 0 - 6.
7.
N or o n ha V, J os hi A, Patil V M, et al. O nce -a-wee k vers us o nce -e ver y- 3-wee ks cis plati n 
c he m ora diati o n f or l ocall y ad va nce d hea d a n d nec k ca ncer: a P hase III ra n d o mize d 
n o ni nferi orit y  trial. J Cli n O nc ol. 2 0 1 8; 3 6( 1 1): 1 0 6 4- 7 2.
8.
Das S, T h o mas S, Pal S K, et al. H y p ofracti o nate d palliati ve ra di ot hera p y  in l ocall y  ad va nce d 
i n o pera ble hea d a n d nec k ca ncer: C M C 
Vell ore 
e x perie nce. I n dia n J Palliat Care. 
2 0 1 3; 1 9( 2): 9 3 - 8.
9.
M osteller 
R D .
Si m plifie d 
Calc ulati o n 
of 
B o d y 
S urface 
Area. 
N 
E n gl 
J Me d 
1 9 8 7; 3 1 7( 1 7): 1 0 9 8 .
1 0. Dr u g De vel o p me nt a n d Dr u g I nteracti o ns. 
htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI ntera
cti o ns La beli n g/ uc m 0 8 0 4 9 9. ht m Accesse d o n 1 4 Ma y 2 0 1 5.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 4 9
1 2
A p pe n dices
A p pe n di x A:
Si g n at ure P a ges a n d Res p o nsi ble Pers o ns f or t he Tri al
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI






M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 4 9
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A n O pe n La bel, P hase Ia/I b Trial of t he D N A -P K 
I n hi bit or M S C 2 4 9 0 4 8 4 A 
i n C o m bi nati o n 
wit h 
Ra di ot hera p y i n Patie nts 
wit h 
A d va nce d 
S oli d 
T u m ors
I N D N u m ber:
E u dr a C T N u m ber
2 0 1 5- 0 0 0 6 7 3- 1 2
Cli nic al Tri al Pr ot oc ol D ate / Versi o n
3 1 Ja n uar y 2 0 1 9 / Versi o n 9. 0
Ce nter N u m ber
Pri nci p al I n vesti g at or
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil f or Har m o nisati o n G o o d Cli nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt h A ut h orit y re q uire me nts a n d nati o nal la ws.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o btai n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I nvesti gati o nal Me dici nal 
Pr o d uct a n d a n y  ot her fi na ncial ties wit h the S p o ns or. T he S p o ns or will use a n y  s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl yi n g wit h t he re g ulat or y re q uire me nts. I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 4 9
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me
F u ncti o n
Bi ostatisticia n
I nstit uti o n
Merc k K Ga A
A d dress
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber
E- mail a d dress
Na me
F u ncti o n
Pri nci pal Cli nical Trial Lea d
I nstit uti o n
Merc k K Ga A
A d dress
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber
E- mail a d dress
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 4 9
A p pe n di x B :  
Res p o nse E v al u ati o n C riteri a i n S oli d T u m ors ( R E CI S T v 1. 1)
F or details, please refer t o t he f oll o wi n g pa per b y Eise n ha uer et al.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
re vise d R E CIS T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5( 2): 2 2 8 - 4 7.
Defi niti o ns
At Baseli ne ( wit hi n 4 wee ks of i nitiati o n of treat me nt), t u m or lesi o ns/l ym p h n o des will be 
cate g orize d meas ura ble or n o n -meas ura ble as f oll o ws:
Me as ur a ble:

T u m or lesi o ns : M ust be acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:

1 0 m m b y  C T sca n ( C T sca n slice t hic k ness ≤ 5 m m), 

1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y m eas ure d 
wit h cali pers s h o ul d be rec or de d as n o n -meas ura ble),

2 0 m m b y  c hest X-ra y.

M ali g n a nt ly m p h n o des : T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l ym p h 
n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y  CT sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o be ≤ 5 m m). At Baseli ne a n d i n f oll o w- u p, o nl y  the s h ort a xis will be meas ure d 
a n d f oll o we d. See als o n otes bel o w o n “ Baseli ne d oc u me ntati o n of tar get a n d n o ntar get lesi o ns” 
f or i nf or mati o n o n ly m p h n o de meas ure me nt.
N o n - me as ur a ble

All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l ym p h 
n o des wit h 1 0 t o < 1 5 m m s h ort a xis) as well as tr uly n o n- meas ura ble lesi o ns. Lesi o ns 
c o nsi dere d tr ul y n o n -meas ura ble i ncl u de le pt o me ni n geal disease, ascites, ple ural or pericar dial 
eff usi o n, i nfla m mat or y breast disease, l ym p ha n gitic 
i n v ol ve me nt of s ki n or l u n g, a n d 
a b d o mi nal masses/a b d o mi nal or ga n o me ga l y ide ntifie d b y  ph y sical e xa m t hat is n ot meas ura ble 
b y  re pr o d uci ble i ma gi n g tec h ni q ues.
S peci al c o nsi der ati o ns re g ar di n g lesi o n me as ur a bilit y
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y  treate d wit h l ocal t hera p y re q uire partic ular 
c o m me nt: 
B o ne lesi o ns:

B o ne sca n, p ositr o n e missi o n t o m o gra p hy sca n, or plai n fil ms are n ot c o nsi dere d a de q uate 
i ma gi n g tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m 
t he prese nce or disa p peara nce of b o ne lesi o ns. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 4 9

L yt ic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifia ble s oft tiss ue c o m p o ne nts, t hat 
ca n be e val uate d b y  cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T, M RI, or ot her esta blis he d 
met h o ds ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he 
defi niti o n of meas ura bilit y descri be d a b o ve.

Blastic b o ne lesi o ns are n o n meas ura ble.
Cystic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be c o nsi dere d 
as mali g na nt lesi o ns ( neit her meas ura ble n or n o n meas ura ble) beca use t he y are, b y  defi niti o n, 
si m ple c ysts. 

‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble lesi o ns, 
if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, if n o nc ystic lesi o ns are 
pr ese nt i n t he sa me s u bject, t hese are preferre d f or selecti o n as tar get lesi o ns.
Lesi o ns wit h pri or l oc al tre at me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y  irra diate d area or ot her l oc ore gi o nal t hera py area are 
us uall y  not c o nsi dere d meas ura ble u nless t here has bee n de m o nstrate d pr o gressi o n i n t he lesi o n. 
Trial pr ot oc ols s h o ul d detail t he c o n diti o ns u n der w hic h s uc h lesi o ns w o ul d be c o nsi dere d 
meas ura ble.
Met h o ds of me as ure me nt

Meas ure me nt of lesi o ns
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, us i n g cali pers if cli nicall y assesse d. 
All baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d 
ne ver m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt.

Met h o d of assess me nt
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at Baseli ne a n d d uri n g f oll o w- u p. I ma gi n g base d e val uati o n 
s h o ul d al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d 
ca n n ot be i ma ge d b ut are assessa ble b y  cli nical e xa m. Cli nical lesi o ns: Cli nical lesi o ns will o nl y 
be c o nsi dere d meas ura ble w he n t he y are s u perficial a n d 1 0 m m dia meter as assesse d usi n g 
cali pers (e. g., s ki n n o d ules). F or t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y 
i ncl u di n g a r uler t o esti mate t he size of t he lesi o n is s u g geste d. As n ote d a b o ve, w he n lesi o ns 
ca n be e val uate d b y b ot h cli nical e xa m a n d i ma gi n g, i ma gi n g e val uati o n s h o ul d be u n derta ke n 
si nce it is m ore o bjecti ve a n d ma y als o be re vie we d at t he e n d of t he trial.

C hest X -r ay: C hest C T is preferre d o ver c hest X- ra y, partic ularl y w he n pr o gressi o n is a n 
i m p orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X- ra y, partic ularl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, lesi o ns o n c hest X- ra y ma y b e co nsi dere d meas ura b le if t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerate d l u n g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 4 9

C T, M RI : C T is t he best c urre ntl y availa ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T 
sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve 
slice t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice 
t he slice t hic k ness. A n M RI is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y scans).

Ultr as o u n d : Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as 
a met h o d of meas ure me nt.

E n d osc o py, l a p ar osc o py : T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n 
is n ot a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n 
bi o psies are o btai ne d or t o deter mi ne rela pse i n trials w here rec urre nce f oll o wi n g C R or 
s ur gical resecti o n is a n e n d p oi nt.

T u m or m arkers : T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. 

Cyt ol o gy, hist ol o gy : T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n 
rare cases if re q uire d b y pr ot oc ol (f or e xa m ple, resi d ual lesi o ns i n t u m or t y pes s uc h as ger m 
cell t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n 
t o be a p ote ntial a d verse effect of treat me nt (e. g., wit h certai n ta xa ne c o m p o u n ds or 
a n gi o ge nesis i n hi bit ors), t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n 
t hat a p pears or w orse ns d uri n g treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met 
criteria f or res p o nse or sta ble disease i n or der t o differe ntiate bet wee n res p o nse ( or sta ble 
disease) a n d pr o gressi ve disease.
T u m or res p o nse ev al u ati o n
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y  to esti mate t he o verall t u m or 
b ur de n at Baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. O nl y  s u bjects wit h 
meas ura ble disease at Baseli ne s h o ul d be i ncl u de d i n pr ot oc ols w here o bjecti ve t u m or res p o nse is 
t he pri mar y  en d p oi nt. Meas ura ble di sease is defi ne d b y  the prese nce of at least o ne meas ura ble 
lesi o n. Res p o nse criteria are liste d i n Ta ble E. 1 a n d Ta ble E. 2 . 
Res p o nse Criteri a
T a ble E. 1
E v al u ati o n of t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R)  
Di s a p p e ar a n c e of all t ar g et l e si o n s. A n y p at h ol o gi c al l y m p h n o d e s ( w h et h er t ar g et or 
n o nt ar g et) m u st h a v e r e d u cti o n i n s h ort a xi s t o < 1 0 m m.
P arti al R e s p o n s e ( P R)
At l e a st a 3 0 % d e cr e a s e i n t h e s u m of di a m et er s of t ar g et l e si o n s, t a ki n g a s 
r ef er e n c e t h e b a s eli n e s u m di a m et er s.
Pr o gr e s si v e Di s e a s e 
At l e a st a 2 0 % i n cr e a s e i n t h e s u m of di a m et er s of t ar g et l e si o n s, t a ki n g a s r ef er e n c e 
t h e s m all e st s u m o n tri al (t hi s i n cl u d e s t h e b a s eli n e s u m if t h at i s t h e s m all e st o n 
tri al). I n a d diti o n t o t h e r el ati v e i n cr e a s e of 2 0 %, t h e s u m m u st al s o d e m o n str at e a n 
a b s ol ut e i n cr e a s e of at l e a st 5 m m. ( N ot e: t h e a p p e ar a n c e of o n e or m or e n e w 
l e si o n s i s al s o c o n si d er e d pr o gr e s si o n).
St a bl e Di s e a s e 
N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f o r P R n or s uffi ci e nt i n cr e a s e t o q u alif y f or 
pr o gr e s si v e di s e a s e, t a ki n g a s r ef er e n c e t h e s m all e st s u m di a m et er s w hil e o n tri al
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 4 9
T a ble E. 2
E v al u ati o n of n o nt ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R)
Di s a p p e ar a n c e of all n o nt ar g et l e si o n s a n d n or m ali z ati o n of t u m or m ar k er l e v el. All 
l y m p h n o d e s m u st b e n o n p at h ol o gi c al i n si z e ( < 1 0 m m s h ort a xi s).
St a bl e Di s e a s e 
P er si st e n c e of o n e or m or e n o nt ar g et l e si o n( s) a n d/ or m ai nt e n a n c e of t u m or m ar k er 
l e v el a b o v e t h e n or m al li mit s.
Pr o gr e s si v e Di s e a s e 
U n e q ui v o c al pr o gr e s si o n ( s e e c o m m e nt s b el o w) of e xi sti n g n o nt ar g et l e si o n s. ( N ot e: 
t h e a p p e ar a n c e of o n e or m or e n e w l e si o n s i s al s o c o n si d er e d pr o gr e s si o n).
N ot e: Alt h o u g h a cl e ar pr o gr e s si o n of “ n o nt ar g et” l e si o n s o nl y i s e x c e pti o n al, i n s u c h cir c u m st a n c e s, t h e o pi ni o n of 
t h e tr e ati n g p h y si ci a n s h o ul d pr e v ail a n d t h e pr o gr e s si o n st at u s s h o ul d b e c o nfir m e d l at er o n b y t h e r e vi e w p a n el 
( or tri al c h air).
E v al u ati o n of best o ver all res p o nse
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse assess me nt occ urs.  Ta ble E- 3
bel o w pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or s u bjects 
w h o ha ve meas ura ble disease at baseli ne.
T a ble E - 3
T ar g et l e si o n s
N o nt ar g et l e si o n s
N e w  l e si o n s
O v er all r e s p o n s e
C R
C R
N o
C R
C R
N o n -C R/ n o n -pr o gr e s si v e 
di s e a s e
N o
P R
C R
N ot e v al u at e d
N o
P R
P R
N o n - pr o gr e s si v e di s e a s e 
or n ot all e v al u at e d
N o
P R
St a bl e di s e a s e
N o n - pr o gr e s si v e di s e a s e 
or n ot all e v al u at e d
N o
St a bl e di s e a s e
N ot all e v al u at e d
N o n pr o gr e s si v e di s e a s e
N o
N E
Pr o gr e s si v e di s e a s e
A n y
Y e s or N o
Pr o gr e s si v e di s e a s e
A n y
Pr o gr e s si v e di s e a s e
Y e s or N o
Pr o gr e s si v e di s e a s e
A n y
A n y
Y e s
Pr o gr e s si v e di s e a s e
A b br e vi ati o n s: C R = c o m pl et e r e s p o n s e, N E = n ot e v al u a bl e; P R = p arti al r e s p o n s e.
T he best o verall res p o nse is deter mi ne d o nce all t he data f or t he s u bject is k n o w n.
Best res p o nse deter mi nati o n i n trials w here c o nfir mati o n of C R or P R I S N O T re q uire d: Best 
res p onse i n t hese trials is defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a s u bject 
w h o has sta ble disease at first assess me nt, P R at sec o n d assess me nt, a n d pr o gressi ve disease o n 
last assess me nt has a best o verall res p o nse of P R). W he n sta ble disease is belie ve d t o be best 
res p o nse, it m ust als o meet t he pr ot oc ol s pecifie d mi ni m u m ti me fr o m baseli ne. If t he mi ni m u m 
ti me is n ot met w he n sta ble disease is ot her wise t he best ti me p oi nt res p o nse, t he s u bject’s best 
res p o nse de pe n ds o n t he s u bse que nt assess me nts. F or e xa m ple, a s u bject w h o has sta ble disease at 
first assess me nt, pr o gressi ve disease at sec o n d a n d d oes n ot meet mi ni m u m d urati o n f or sta ble 
disease, will ha ve a best res p o nse of pr o gressi ve disease. T he sa me s u bject l ost t o f oll o w -u p a fter 
t he first sta ble disease assess me nt w o ul d be c o nsi dere d n ot e val ua ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 4 9
Best res p o nse deter mi nati o n i n trials w here c o nfir mati o n of C R or P R I S re q uire d: C o m plete or 
partial res p o nses ma y be clai me d o nl y if t he criteria f or eac h are met at a s u bse q ue nt ti me p oi nt as 
s pecifie d i n t he pr ot oc ol (at least 4 wee ks a part). I n this circ u msta nce, t he best o verall res p o nse 
ca n be i nter prete d as i n  Ta ble E - 4.
T a ble E -4
O v er all r e s p o n s e  
O v er all r e s p o n s e
B E S T o v er a ll r e s p o n s e
Fir st ti m e p oi nt
S u b s e q u e nt ti m e p oi nt
C R
C R
C R
C R
P R
St a bl e di s e a s e, pr o gr e s si v e di s e a s e, or P R a
C R
St a bl e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
C R
Pr o gr e s si v e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
C R
N E
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e N E
P R
C R
P R
P R
P R
P R
P R
St a bl e di s e a s e
St a bl e di s e a s e
P R
Pr o gr e s si v e di s e a s e
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e, pr o gr e s si v e di s e a s e
P R
N E
St a bl e di s e a s e pr o vi d e d mi ni m u m crit eri a f or st a bl e 
di s e a s e d ur ati o n m et, ot h er wi s e N E
N E
N E
N E
A b br e vi ati o n s: C R = c o m pl et e r e s p o n s e, N E = n ot e v al u a bl e, P R = p arti al r e s p o n s e, 
a
If a C R i s tr ul y m et at fir st ti m e p oi nt, t h e n a n y di s e a s e s e e n at a s u b s e q u e nt ti m e p oi nt, e v e n di s e a s e 
m e eti n g P R crit eri a r el ati v e t o b a s eli n e, m a k e s t h e di s e a s e pr o gr e s si v e di s e a s e at t h at p oi nt ( si n c e di s e a s e m u st 
h a v e r e a p p e ar e d aft er C R). B e st r e s p o n s e w o ul d d e p e n d o n w h et h er mi ni m u m d ur ati o n f or st a bl e di s e a s e w a s 
m et. H o w e v er, s o m eti m e s ‘ C R’ m a y b e cl ai m e d w h e n s u b s e q u e nt s c a n s s u g g e st s m all l e si o n s w er e li k el y still 
pr e s e nt a n d i n f a ct t h e s u bj e ct h a d P R, n ot C R at t h e fir st ti m e p oi nt. U n d er t h e s e cir c u m st a n c e s, t h e ori gi n al C R 
s h o ul d b e c h a n g e d t o P R a n d t h e b e st r e s p o n s e i s P R.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 4 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 4 9
A p pe n di x D:
O utli ne of I nte nsit y -m o d ul ate d R a di ot her a p y
I n t he pla n ni n g of R T, i nte nsit y mo d ulate d R T (I M R T) m ust be use d. T he d ose pla n ni n g ca n be 
C T or p ositr o n e missi o n t o m o gra p h y- C T ( P E T - C T) acc or di n g t o i nstit uti o nal g ui deli nes.
T he use of dail y i ma ge g ui de d R T (I G R T) is rec o m me n de d.
F or patie nts wit h S C C H N, t he t otal d ose of R T is 6 6 t o 7 0 G y  gi ve n i n 3 3 t o 3 5 fracti o ns a n d f or 
patie nts wit h N S C L C, t he t otal d ose of R T is 6 6 G y gi ve n i n 3 3 fracti o ns. Si m ulta ne o us i nte grate d 
or se q ue ntial b o ost s h o ul d be gi ve n acc or di n g t o i nstit uti o nal g ui deli nes.
Or g a ns at ris k t o be c o nt o ure d
S C C H N:
P ar oti d gl a n d
R e q uir e d
S pi n al c or d
R e q uir e d
O pti c c hi a s m
R e q uir e d
Br ai n st e m
R e q uir e d
Or al c a vit y
F a c ult ati v e
Br a c hi al pl e x u s
F a c ult ati v e
M a n di bl e
F a c ult ati v e
P h ar y n g e al c o n stri ct or m u s cl e
F a c ult ati v e
C o c hl e a
F a c ult ati v e
E s o p h a g u s
F a c ult ati v e
L u n g s
F a c ult ati v e
E xt er n al b or d er of p ati e nt s
F a c ult ati v e
N S C L C:
S pi n al c or d
R e q uir e d
Br a c hi al pl e x u s
F a c ult ati v e
H e art
R e q uir e d
C or o n ar y art eri e s
R e q uir e d
St o m a c h, li v er a n d k i d n e y (if i n cl u d e d i n 
fi el d)
R e q uir e d
E s o p h a g u s
R e q uir e d
L u n g s
R e q uir e d
E xt er n al b or d er of p ati e nt s
R e q uir e d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 4 9
A p pe n di x E:
C o ntr ace pti ve G ui d a nce a n d W o me n of C hil d be ari n g P ote nti al
Defi niti o ns
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y 
sterile. 
Per ma ne nt 
sterilizati o n 
met h o ds 
i ncl u de h ys terect o my, 
bilateral 
sal pin gect o m y , a n d bilateral o o p h orect o my.
W o me n i n t he f oll o wi n g c ate g ories are n ot c o nsi dere d W O C B P
1.
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:

D oc u me nte d h ys terect o m y

D oc u me nte d bilateral sal pi n gect o m y

D oc u me nte d bilateral o o p h orect o m y
N ote:  Doc u me ntati o n ca n c o me fr o m t he site pers o n nel’s: re vie w of partici pa nt’s me dical 
rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w.
2.
Pre me narc hal
3.
P ost me n o pa usal fe male

Fe males w h o are p ost me n o pa usal (a ge-relate d a me n orr hea ≥1 2 c o nsec uti ve m o nt hs a n d 
i ncrease d f ollicle-sti m ulati n g h or m o ne [ F S H] > 4 0 mI U/ m L), or w h o ha ve u n der g o ne 
h y sterect o my or bilateral o o p h orect o m y  are e xe m pt fr o m pre g na nc y testi n g. If necessar y t o 
c o nfir m p ost me n o pa usal stat us, a n F S H will be dra w n at Scr ee ni n g.

Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of t he 
n o n- h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T 
d uri n g t he trial. Ot her wise, 
t he y 
must disc o nti n ue H R T 
t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore trial e nr oll me nt.
C o ntr ace pti ve G ui d a nce
Hi g hl y  Eff e cti v e C o ntr a c e pti v e M et h o d s T h at Ar e U s er D e p e n d e nt 
F ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 

C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g ) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n b

or al 

i ntr a v a gi n al 

tr a n s d er m al 

Pr o g e st o g e n -o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b

or al 

i nj e ct a bl e
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M 3 8 1 4 ( M S C 2 4 9 0 4 8 4 A )
P h ase I T ri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 4 9
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er I n d e p e n d e nt 

I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b

I ntr a ut eri n e d e vi c e (I U D)

I ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S)

bil at er al t u b al o c cl u si o n

V a s e ct o mi z e d p art n er 
( A v a s e ct o mi z e d p art n er i s a hi g hl y eff e cti v e c o ntr a c e pti o n m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e m al e s e x u al 
p art n er of t h e W O C B P a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. If n ot, a n a d diti o n al hi g hl y eff e cti v e m et h o d of 
c o ntr a c e pti o n s h o ul d b e u s e d. )

S e x u al a b sti n e n c e 
( S e x u al a b sti n e n c e i s c o n si d er e d a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m h et er o s e x u al i nt er c o ur s e 
d uri n g t h e e ntir e p eri o d of ri s k a s s o ci at e d wit h t h e tri al dr u g. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e 
e v al u at e d i n r el ati o n t o t h e d u r ati o n of t h e tri al a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p arti ci p a nt.) 
N O T E S: 
a) T y pi c al u s e f ail ur e r at e s m a y diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. U s e s h o ul d b e c o n si st e nt wit h 
o c al r e g ul ati o n s r e g ar di n g t h e u s e of c o ntr a c e p ti v e m et h o d s f or p arti ci p a nt s p arti ci p ati n g i n cli ni c al st u di e s. 
b) H or m o n al c o ntr a c e pti o n m a y b e s u s c e pti bl e t o i nt er a cti o n wit h t h e tri al dr u g, w hi c h m a y r e d u c e t h e effi c a c y of t h e 
c o ntr a c e pti v e m et h o d. I n t hi s c a s e 2 hi g hl y eff e cti v e m et h o d s of c o ntr a c e pti o n s h o ul d b e utili z e d d uri n g t h e tr e at m e nt 
p eri o d a n d f or at l e a st 9 0 d a y s aft er t h e l a st d o s e of tri al tr e at m e nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

SAP_001.pdf: 
M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 6 0
I nte gr ate d A n al ysis Pl a n
P h ase I a
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o.
E M R 1 0 0 0 3 6 - 0 0 2
Title
A n O pe n La bel, P hase Ia/I b Trial of t he D N A -P K I n hi bit or 
M S C 2 4 9 0 4 8 4 A i n C o m bi nati o n wit h Ra di ot hera p y  in Patie nts 
wit h A d va nce d S oli d T u m ors
Tri al P h ase
Ia/I b ( wit h an a ncillar y cli nical Pr o of- of- Pri nci ple part )
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)
M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
Cli nic al Tri al Pr ot oc ol 
Versi o n
3 1 Ja n uar y  2 0 1 9 / Versi o n 9. 0
Inte gr ate d A n al ysis Pl a n 
A ut h or
C o or di n ati n g A ut h or
Bi o st ati sti c s, M er c k H e alt h c ar e K G a A
F u n cti o n
A ut h or( s) / D at a A n al y s t( s)
Bi o st ati sti c s, 
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
1 8 A u g ust 2 0 2 0 / Versi o n 3. 0
Inte gr ate d A n al ysis Pl a n 
Re vie wers
F u n cti o n
N a m e
Bi o st ati sti c s, 
Bi o st ati sti c s, 
, M er c k H e alt h c ar e K G a A
M e di c al L e a d, M er c k
H e alt h c ar e K G a A
, M er c k
H e alt h c ar e K G a A
 M er c k H e alt h c ar e 
K G a A
, E M D S er o n o
 E M D S er o n o
C o nfi de nti al
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 2 0 b y Merc k K G a A, D ar mst a dt, Ger m a n y or its aff ili ate. All ri g hts reser ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 6 0
S i g n at ure P a ge
I nte gr ate d A n al ysis Pl a n: E M R 1 0 0 0 3 6 - 0 0 2
A n O pe n La bel, P hase Ia/I b Trial of t he D N A -P K I n hi bit or M S C 2 4 9 0 4 8 4 A i n C o m bi nati o n wit h 
Ra di ot hera p y i n Patie nts wit h A d va nce d S oli d T u m ors
A p pr o val of t he I A P b y  all Merc k Data A nal ys is Res p o nsi ble is d oc u me nte d wit hi n E L D O R A D O. 
Wit h t he a p pr o val wit hi n El d ora d o, t he Merc k res p o nsi ble f or eac h of t he a nal ys is als o ta kes 
res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a de q uately.
Merc k res p o nsi ble
, Bi ostatistics
Via E L D O R A D O a p pr o val pr ocess
 
Via E L D O R A D O a p pr o val pr ocess
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D
P P D


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 6 0
1
T a ble of C o nte nts
I nte grate d A nalys is Pla n P hase Ia........................................................................................ 1
Si g nat ure Pa ge
.............................................................................................................. 2
1
Ta ble of C o nte nt s.................................................................................. 3
2
List of A b bre viati o ns a n d Defi niti o n of Ter ms .................................... 5
3
M o dificati o n Hist or y
............................................................................ 8
4
P ur p ose of t he I nte grate d A nal y sis Pla n ............................................... 9
5
O bjecti ves a n d E n d p oi nts ..................................................................... 9
6
O ver vie w of Pla n ne d A nal y ses........................................................... 1 0
6. 1
Sec o n dar y  safety a nal ysis ................................................................... 1 0
6. 2
Fi nal A nal ys is..................................................................................... 1 0
7
C ha n ges t o t he Pla n ne d A nal y ses i n t he Cli nical Trial Pr ot oc ol........ 1 1
7. 1
C O VI D -1 9 I m pact .............................................................................. 1 1
8
Pr ot oc ol De viati o ns a n d A nal y sis Sets ............................................... 1 1
8. 1
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ys is Sets ......................... 1 1
8. 2
Defi niti o n of A nal ys is Sets a n d S u b gr o u ps........................................ 1 2
9
Ge neral S pecificati o ns f or Data A nal y ses .......................................... 1 3
1 0
Trial S u bjects ...................................................................................... 1 7
1 0. 1
Dis p ositi o n of S u bjects a n d Disc o nti n uati o ns .................................... 1 7
1 0. 2
Pr ot oc ol De viati o ns ............................................................................ 1 9
1 0. 2. 1
I m p orta nt Pr ot oc ol De viati o ns............................................................ 1 9
1 0. 2. 2
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal y sis Set ................... 2 0
1 1
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................. 2 0
1 1. 1
De m o gra p hics ..................................................................................... 2 0
1 1. 2
Me dical Hist or y .................................................................................. 2 1
1 1. 3
Ot her B aseli ne C haracteristics ............................................................2 1
1 2
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ............................. 2 2
1 2. 1
Pri or A nti -Ca ncer Treat me nts a n d pr oce d ures ...................................2 2
1 2. 2
Pre vi o us Me dicati o ns ..........................................................................2 3
1 2. 3
C o nc o mita nt Me dicati o ns................................................................... 2 3
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 6 0
1 2. 4
C o nc o mita nt Pr oce d ures .....................................................................2 4
1 2. 5
A nti- ca ncer p ost -treat me nt ................................................................. 2 4
1 3
Treat me nt C o m plia nce a n d E x p os ure ................................................. 2 4
1 4
Efficac y  A nalys es ............................................................................... 2 7
1 4. 1
Best O verall Res p o nse ........................................................................ 2 7
1 5
Safet y  A nalys es .................................................................................. 3 0
1 5. 1
D L T ( Pri mar y  e n d p oi nt)..................................................................... 3 0
1 5. 2
A d verse E ve nts ................................................................................... 3 0
1 5. 2. 1
All A d verse E ve nts ............................................................................. 3 1
1 5. 2. 2
A d verse E ve nts Lea di n g t o Treat me nt Disc o nti n uati o n ..................... 3 4
1 5. 2. 3
Late t o xicities ...................................................................................... 3 5
1 5. 3
Deat h s, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E ve nts ................................................................................... 3 5
1 5. 3. 1
Deat hs ................................................................................................. 3 5
1 5. 3. 2
Seri o us A d verse E ve nts ...................................................................... 3 6
1 5. 3. 3
Ot her Si g nifica nt A d verse E ve nt ........................................................ 3 6
1 5. 4
Cli nical L a b orat or y E val uati o n........................................................... 3 6
1 5. 5
Vital Si g ns .......................................................................................... 3 9
1 5. 6
Ot her Safet y or T olera bilit y  E val uati o ns............................................ 4 0
1 5. 6. 1
Macr osc o pic si g ns of blee di n g ........................................................... 4 0
1 5. 6. 2
E C O G Perf or ma nce Stat us ................................................................. 4 0
1 5. 6. 3
E C G a n d Q T/ Q Tc e val uati o ns ............................................................ 4 0
1 5. 6. 4
Pre g na nc y  Test.................................................................................... 4 1
1 6
A nal y ses of Ot her E n d p oi nts ..............................................................4 2
1 6. 1
P har mac o ki netics ................................................................................ 4 2
............................................4 6
............................................4 6
1 7
Refere nces ...........................................................................................4 7
1 8
A p pe n dices .........................................................................................4 7
A p pe n di x 1: I m p orta n t Pr ot oc ol De viati o ns...................................................................... 4 7
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 6 0
2
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms
A E
A d verse E ve nt
A L L
All s u bjects ( A nal ys is set)
A T C
A nat o mical T hera pe utic C he mical
A U C 0 - ∞
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o e xtra p olate d t o 
i nfi nit y
A U C 0 -t
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
B M K
Bi o ma r ker
B O R
Best O verall Res p o nse
B S A
B o d y S urface Area
c P o P
cli nical Pr o of- of-Pri nci ple
C L /f
Oral cleara nce
C L ss/f
Oral cleara nce at stea d y s tate
C R
C o m plete Res p o nse
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n
C O VI D - 1 9 
C or o na vir us disease 2 0 1 9
C R O
C o ntract Researc h Or ga nizati o n
C R T
C he m ora di ot hera p y
C T C
C o m m o n Ter mi n ol o g y  Criteria
C T M S
Cli nical Trial Ma na ge me nt S y ste m
C T R
Cli nical Trial Re p ort
D E
D ose Escalati o n ( A nal ys is set)
D L T
D ose L i miti n g T o xicit y
P B M C
Peri p heral Bl o o d M o n o n uclear Cell
E C G
Electr ocar di o gra m
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 6 0
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us
e C R F
electr o nic Case Re p ort F or m
F A S
F ull A nal ys is Set
F D
Fracti o n Da y
F U
F oll o w - u p
G C P
G o o d Cli nical Practice
H C G
H u ma n C h ori o nic G o na d otr o pi n
H P V
H u ma n Pa pill o ma Vir us
I A P
I nte grate d A nalys is Pla n
I CF
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
L L O Q
L o wer Li mit of Q ua ntificati o n
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M T D  
Ma xi m u m T olerate d D ose
N CI -C T C A E
Nati o nal Ca ncer I nstit ute – C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts
N E
N ot E val ua ble
P D
Pr o gressi ve Disease
P K
P har mac o ki netic(s)
P R
Partial Res p o nse
P T
Preferre d Ter m
Q 1
First Q uartile
Q 3
T hir d Q uartile
Q D
O nce dail y
Q Tc F
Fri dericia -c orrecte d Q T i nter val
R acc A U C 0 - 4
Acc u m ulati o n rati o f or A U C 0- 4
R acc [ Cma x ]
Acc u m ulati o n rati o f or ma xi m u m c o nce ntrati o n
R E CI S T
Res p o nse E val uati o n Criteria I n S oli d T u m ors
R P 2 D
Rec o m me n de d P hase II D ose
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 6 0
R T
Ra di ot hera p y
S A E
Seri o us A d verse E ve nt
S A F
Safet y  ( A nalys is set)
S A P
Statistical A nal y sis Pla n
S D
Sta ble Disease
S d
Sta n dar d De viati o n
S D T M
St u d y  Data Ta b ulati o n M o del
S M C
Safet y  M o nit ori n g C o m mittee
S O C
S y ste m Or ga n Class
T E A E
Treat me nt E mer ge nt A d verse E ve nt
t1/ 2
A p pare nt ter mi nal half -life
tma x
Ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n
U L N
U p per Li mit of N or mal
Vz/f
A p pare nt v ol u me of distri b uti o n d uri n g ter mi nal p hase
Vss/f
A p pare nt v ol u me of  distri b uti o n at stea d y  state
W H O -D D
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI




M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 6 0
4
P ur p ose of t he I nte gr ate d A n al ysis Pl a n
T he p ur p ose of t his IA P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or all a nal ys es of 
data c ollecte d f or pr ot oc ol E M R 1 0 0 0 3 6 - 0 0 2 f or t he P hase Ia ( d ose escalati o n part) . Res ults of t he 
a nal ys es descri be d i n t his I AP will be i ncl u de d i n t he Cli nical Trial Re p ort ( C T R). A d diti o nall y , 
t he pla n ne d a nal yses i de ntifie d i n t his IA P will be i ncl u de d i n re g ulat or y su b missi o ns or f ut ure 
ma n u scri pts. A n y  post -h oc, or u n pla n ne d a nal yses perf or me d t o pr o vi de res ults f or i ncl usi o n i n 
t he C T R b ut n ot i de ntifie d i n t his pr os pecti ve IA P will be clearl y i de ntifie d i n t he C T R. 
T he IA P is base d u p o n secti o n 8 ( Statistics) of t he trial pr ot oc ol a n d pr o t oc ol a me n d me nts a n d is 
pre pare d i n c o m plia nce wit h I C H E 9. 
A se parate IA P will d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he a nal ys is t o pr o vi de t o 
t he S M C me m bers pri or t o eac h S M C meeti n g f or t he d ose escalati o n p hase of P hase Ia. 
A d diti o nall y, se parate d I A Ps will be iss ue d f or t he P hase I b (e x pa nsi o n part) a n d t he a ncillar y 
c P O P part of t he trial .
5
O bjecti ves a n d E n d p oi nts
O bj e cti v e
E n d p oi nt
I A P 
s e cti o n
P ri m ar y
O bj e cti v e
T o d et er mi n e t h e m a xi m u m t ol er at e d d o s e ( M T D) a n d 
r e c o m m e n d e d P h a s e II d o s e ( R P 2 D) of M 3 8 1 4
i n 
c o m bi n ati o n wit h R T ( Ar m A) a n d C R T ( Ar m B)
Pri m ar y E n d p oi nt

D L T
1 5. 1
S e c o n d ar y  
O bj e cti v e
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of M 3 8 1 4
i n c o m bi n ati o n wit h R T ( Ar m A) a n d C R T ( Ar m B)
S e c o n d ar y E n d p oi nt

A E

L a b or at or y v al u e s

Vit al si g n s

M a cr o s c o pi c 
si g n s of bl e e di n g

E C O G

E C G
1 5. 2
1 5. 4
1 5. 5
1 5. 6. 1
1 5. 6. 2
1 5. 6. 3
T o e x pl or e t h e a ntit u m or a cti vit y of M 3 8 1 4 i n 
c o m bi n ati o n wit h R T ( Ar m A) a n d C R T ( Ar m B)
S e c o n d ar y E n d p oi nt

B O R

T u m or si z e 
m e a s ur e m e nt s
1 4. 1
1 4. 1
T o a s s e s s t h e p h ar m a c o ki n eti c s ( P K) of M 3 8 1 4

P h ar m a c o ki n eti c 
p ar a m et er s of 
M 3 8 1 4
1 6. 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 /6 0
6
O ver vie w of Pl a n ne d A n al yses
Statistical a nal yses will be perf or me d usi n g e C R F data o btai ne d u ntil cli nical c ut-off dates as 
descri be d bel o w.
I n t he P hase Ia, t he Safet y  Mo nit ori n g C o m mittee ( S M C) will deci de o n D L Ts rele va nt f or t he 
treat me nt a n d will deci de b y  co nse ns us o n d ose escalati o n, d ose de -escalati o n, e xte nsi o n at sa me 
d ose le vel, or s us pe nsi o n of e nr oll me nt base d o n safet y a n d P K data .
T he c ut-off date f or d ose escalati o n assess me nts will be tri g gere d b y  the c o m pleti o n of t he D L T 
peri o d of t he last s u bject i n t he res pecti ve c o h ort. F or eac h S M C meeti n g, a data s na ps h ot will be 
ta ke n fr o m t he cli nical data base. A de dicate d I A P pr o vi des m ore details f or t he a nal ys is t o be se nt 
t o S M C me m bers pri or t o eac h S M C meeti n g.
T his I A P c o vers t he a nal y ses f or efficac y a n d safet y of t w o milest o nes:
-
Sec o n dar y  safety a nal ysis
-
Fi nal a nal ys is  
6. 1
Sec o n d ar y s afet y a n al ysis
C ut -off d ate:
T his I A P c o vers t he a nal yses f or efficac y an d safet y base d o n t he data c ut -off (see als o c ha pter 9 
Data ha n dli n g after c ut-off date). Statistical a nal yses will be perf or me d usi n g clea ne d e C R F data 
gai ne d u p t o a cli nical c ut-off date w hic h is deter mi ne d w he n last s u bject ha s reac he d t he sec o n d 
p ost -treat me nt t u m or assess me nt. 
T he c ut-off date is deter mi ne d o nce a data e xtract ( bef ore data base l oc k) is a vaila ble w hic h 
i n dicates t hat t he last s u bject has reac he d t he sec o n d p ost -treat me nt t u m or assess me nt. T he cli nical 
c ut-of f date will be t he date o n w hic h acc or di n g t o t his data e xtract t he last s u bject has reac he d t he 
sec o n d p ost-treat me nt t u m or assess me nt.
6. 2
Fi n al A n al ysis
C ut -off d ate:
All fi nal, pla n ne d a nal yses i de ntifie d i n t he Cli nical Trial Pr ot oc ol a n d i n t his I A P will
be 
perf or me d o nl y after t he last s u bject has c o m plete d o ne ye ar of f oll o w- u p, all data q ueries res ol ve d, 
a n d t he data base l oc ke d.
A data re vie w meeti n g will be hel d pri or t o data base l oc k. I n ad diti o n, n o data base ca n be l oc ke d 
u ntil t his I AP has bee n a p pr o ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 /6 0
7
C h a n ges t o t he Pl a n ne d A n al yses i n t he Cli nic al Tri al Pr ot oc ol
T he pr ot oc ol s pecifies t he f oll o wi n g P K para meters t o be re p orte d f or Fracti o n Da y  10: C L ss/f, 
Vss/f , A U C 0-t, a n d A U C T hese will n ot be calc ulate d or re p orte d d ue t o t he li mite d n u m ber of 
P K sa m ples t o be c ollecte d i n t he ter mi nal p hase lea di n g t o u nrelia ble para meter esti mates , please 
refer t o Secti o n 1 6. 1 f or a c o m plete list of P K pa ra meters w hic h will be re p orte d. I n a d diti o n, 
sta n dar d err or of t he mea n will n ot be a descri pti ve statistic use d t o descri be P K varia bles.
I n secti o n 8. 5. 4. 3 of t he pr ot oc ol t he f oll o wi n g a nal ysis is descri be d re gar di n g data c o mi n g fr o m 
t he p h y sical e xa minati o n: “ Data will be f urt her a nal yze d usi n g c o nce ntrati o n effect m o deli n g f or 
baseli ne -c orrecte d Q Tc F val ues o btai ne d at D a y  1.” T his a nal ysis will n ot be perf or me d s o will 
n ot be i ncl u de d i n t his a nal ysis pla n. 
I n t he pr ot oc ol a n u m ber of bi o mar ker a nal ys is sets are defi ne d. T hese will n ot be use d a n d i nstea d 
t he S A F a nalys is set will be use d f or bi o mar ker a nal yses. 
7. 1
C O VI D -1 9 I m p act
A d diti o nal listi n gs will be ge nerate d t o assess p ote ntial i m pacts of C O VI D - 1 9 t o t his st u d y 
i ncl u di n g: 

listi n g of p artici pa nts p ote ntiall y  affecte d b y pa n de mic a n d wit h a n y AEs or P Ds relate d t o 
C O VI D - 1 9

listi n g of P Ds relate d t o C O VI D- 1 9

listi n g of A Es relate d t o C O VI D - 1 9.
8
Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
8. 1
Defi niti o n of Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
I m p orta nt pr ot oc ol de viati o ns are pr ot oc ol de viati o ns t hat mi g ht 
si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y affect a 
s u bject's ri g hts, safety, or well -bei n g. 
I m p orta nt pr ot oc ol de viati o ns will be cate g orize d i n t o o ne of t he f oll o wi n g:

S u bject e nr olle d a n d d ose d o n t he st u d y  w h o di d n ot satisf y e nr ol me nt criteria

S u bject f ulfills wit h dra wal criteria w hilst o n t he st u d y  b ut is n ot wit h dra w n

S u bject is a d mi nistere d t he wr o n g treat me nt or a n i n c orrect d ose

S u bject is a d mi nistere d or ta kes c o nc o mita nt me dicati o n e xcl u de d b y  t he C T P

Fail ure t o c ollect data necessar y  t o i nter pret pri mar y e n d p oi nts

Fail ure t o c ollect necessar y  k e y safet y data
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 /6 0

De viati o ns fr o m g o o d cli nical practice (e. g. de viati o ns relate d t o i nf or me d c o nse nt of 
st u d y partici pa nts)

Ot her i m p orta nt pr ot oc ol de viati o ns
All i m p orta nt pr ot oc ol de viati o ns are d oc u me nte d i n S D T M datasets w het her i de ntifie d t hr o u g h 
site m o nit ori n g, me dical re vie w or pr o gra m mi n g.
8. 2
Defi niti o n of A n al ysis Sets a n d S u b gr o u ps
All S u bjects A n al ysis Set ( A L L):
T he All s u bjects ( AL L) a nal ys is set will i ncl u de all t he s u bjects w h o ha ve si g ne d t he I CFs (i.e., 
scree ni n g fail ures pl us s u bjects e nr olle d). 
S afet y A n al ysis Set ( S A F):
T he Safet y a nal ys is set will i ncl u de all s u bjects w h o recei ve at least o ne a d mi nistrati o n of t he trial 
treat me nt (eit her M 3 8 1 4, R T or C is plati n).
F ull A n al ysis Set ( F A S):
T he F ull A nal ys is Set will i ncl u de all s u bjects w h o recei ve at least o ne a d mi nistrati o n of t he trial 
treat me nt.
D ose Esc al ati o n A n al ysis Set ( D E) :
T he D ose Escalati o n ( D E) a nal ys is set will i ncl u de all s u bjects treate d i n d ose escalati o n c o h orts
w h o recei ve at least 8 0 % of M 3 8 1 4 a n d R T pla n ne d d ose a n d c o m plete t he D L T peri o d (t hr o u g h
5 wee ks [ P hase Ia, Ar m A] or 1 2 wee ks [ P hase Ia, Ar m B] after start of M 3 8 1 4 treat me nt). T he 
D E set will als o i ncl u de s u bjects treate d i n d ose escalati o n c o h orts w h o e x perie nce a D L T d uri n g 
t he D L T peri o d re gar dless of t he recei ve d a m o u nt of eac h dr u g. 
P h ar m ac o ki netic s A n al ysis Set ( P K):
T he P K e val uati o n ( P K) a nal ys is set i n P hase Ia a n d P hase I b parts will i ncl u de s u bjects w h o ha ve 
recei ve d at least t he first d ose of t he dr u g a n d pr o vi de d P K sa m ples as per pr ot oc ol f or at least 6 
h o urs f oll o wi n g first d osi n g o n Fract i o n Da y 1. 
T a ble 1: S u m m ar y of a n al yses a n d ass oci ate d a n al ysis set
A n al yses
A L L 
S A F 
F A S
D E
P K
Dis p ositi o n a n d deat hs

Baseli ne Assess me nts

Past a n d C o nc o mita nt T hera pies

C o m plia nce a n d E x p os ure

D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 /6 0
A n al yses
A L L 
S A F 
F A S
D E
P K
Pri mar y e n d p oi nt: D L Ts

Sec o n dar y efficac y e n d p oi nts

Safet y a n d t olera bilit y

Bi o mar ker

P har mac o ki netics

9
Ge ner al S pecific ati o ns f or D at a A n al yses
Statistical a nal y ses will be perf or me d wit h S A S 9.4 or hi g her.
P o oli n g of ce nters:
Beca use of t he a ntici pate d s mall n u m ber of s u bjects e nr olle d i n eac h ce nter, data will be p o ole d 
acr oss ce nters, a n d t he fact or ce nter will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p 
a nal ys es. 
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles:
All o ut p uts will be pr o vi de d f or eac h ar m se paratel y. N o data bet wee n ar ms will be p o ole d, u nless 
ot her wise state d. F or eac h ar m, d ata will be prese nte d b y  f or m ulati o n, d ose le vel a n d o verall u nless 
s pecifie d ot her wise. T he d ose le vel will be defi ne d b y  the pla n ne d d ose of t he c orres p o n di n g 
c o h ort. If se veral c o h orts ha ve sa me d ose le vel, t here will be p o ole d t o get her f or all s u m mar y 
o ut p uts.
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, i.e.

N u m ber a n d perce nta ge of s ubjects ( n ( %)), n u m ber a n d perce nta ge of s u bjects wit h 
missi n g val ues ( Missi n g ( %))

Mea n, 9 5 % c o nfi de nce i nter vals, as a p pr o priate

Sta n dar d de viati o n

Me dia n

Q 1, a n d Q 3

Mi ni m u m, a n d ma xi m u m
If t here are n o missi n g val ues, t his s h o ul d be i n dicate d by a 0 ( 0. 0).
Missi n g statistics, e. g, w he n t he y ca n n ot be calc ulate d, s h o ul d be prese nte d as “ n d”. F or e xa m ple, 
if n = 1, t he sta n dar d de viati o n ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as “ n d”.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 /6 0
Q ualitati ve varia bles will be s u m marize d b y  fre q ue ncies a n d perce nta ges.
U nless ot her wise state d, t he calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of s u bjects of 
t he a nal ysis set of i nterest. T heref ore, c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he 
de n o mi nat or a n d prese nte d as a se parate cate g or y .
Prese nt a ti o n of P K C o nce ntr ati o n D at a
M 3 8 1 4
a n d 
 c o nce ntrati o n data will be descri pti vel y  su m marize d usi n g: n u m ber of n o n-
missi n g o bser vati o ns (n ), arit h metic mea n ( Mea n), sta n dar d de viati o n ( S D), c oefficie nt of 
variati o n ( C V %), mi ni m u m ( Mi n), me dia n ( Me dia n) a n d ma xi m u m ( Ma x). I n n ≤ 2, o nl y  n, Mi n, 
a n d Ma x will be re p orte d.
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce data, a n d r o u n de d f or re p orti n g p ur p oses o nl y. T he f oll o wi n g c o n ve nti o ns 
will be a p plie d w he n re p orti n g descri pti ve statistics of P K c o nce ntrati o n data:
Mea n, Mi n, Me dia n, Ma x : 
3 si g nifica nt di gits
S D:
4 si g nifica nt di gits
C V % :
1 deci mal place 
Prese nt ati o n of P K P ar a meter D at a
P har mac o ki netic para meter data will be descri pti vel y  su m marize d usi n g: n, Mea n, S D, C V %, Mi n, 
Me dia n , Ma x , ge o metric mea n ( Ge o Mea n), a n d t he ge o metric c oefficie nt of variati o n ( Ge o CV). 
F or ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (t ma x ), o nl y n, Mi n, Me dia n, a n d Ma x will be 
re p orte d.
T he P K para meter ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ) will be re p orte d wit h t he sa me 
precisi o n as t he s o urce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures. I n 
e x p ort datasets, as well as i n t he S D T M P P d o mai n, P K para meters will be pr o vi de d wit h f ull 
precisi o n, a n d will n ot be r o u n de d. Descri pti ve statistics of P K para meter data will be calc ulate d 
usi n g f ull precisi o n val ues, a n d r o u n de d f or re p orti n g p ur p oses o nl y . 
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of P K para meter 
data:
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI : 
3 si g nifica nt di gits
S D:
4 si g nifica nt di gits
C V %, Ge o C V %:
1 deci mal place 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 /6 0
Defi niti o n of b aseli ne:
T he last meas ure me nt pri or t o first a d mi nistrati o n of trial treat me nt (eit her M 3 8 1 4 , R T
or 
C is plati n) will be use d as t he baseli ne meas ure me nt.
Defi niti o n of tre at me nt d a y:
Treat me nt Da y  1 is defi ne d as t he date of first a d mi nistrati o n of trial treat me nt ( M 3 8 1 4 a n d/ or R T
a n d/ or C is plati n), t he da y bef ore is defi ne d as Treat me nt D a y –1 ( n o Treat me nt D a y 0 is defi ne d). 
Defi niti o n of o n- tre at me nt e v al u ati o ns f or s afet y a n al yses:
O n -treat me nt e val uati o n s f or safety a nal ys es will be e val uati o ns perf or me d o n or after T reat me nt 
D a y 1 u ntil 3 0 da y s after t he last d ose of trial treat me nt or t he cli nical c ut -off date (if t he treat me nt 
is still o n g oi n g).
Defi niti o n of d ur ati o n:
D urati o n will be calc ulate d b y t he differe nce of start a n d st o p date + 1 (e. g. s ur vi val ti me ( da ys) = 
date of deat h – date of first d ose + 1) , if n ot ot her wise s pecifie d.
C o n versi o n f act ors:
T he f oll o wi n g c o n versi o n fact ors will 
be use d t o c o n vert da y s i nto m o nt hs 
or ye ars: 
1 m o nt h = 3 0. 4 3 7 5 d ays, 1 ye ar = 3 6 5. 2 5 d ays.
D at a h a n dli n g after c ut- off d ate:
Data after c ut-off d o n ot u n der g o t he clea ni n g pr ocess. T he o nl y  exce pti o ns are t he date of deat h 
a n d t he date last k n o w n t o be ali ve. Data o btai ne d after the c ut -off will n ot be dis pla y e d i n a n y 
listi n gs or use d f or s u m mar y statistics (e. g. la b orat or y val ues of sa m ples ta ke n after data c ut-off, 
A E wit h o nset date after data c ut -off, etc. ) will n ot be i ncl u de d i n a n y a nal ysis or listi n g.
F or a n y a d verse e ve nt or c o nc o mita nt me dicati o n starti n g bef ore t he c ut -off date, t he e n d date will 
n ot be i m p ute d (e ve n if t he e n d date is after t he c ut -off date) a n d will be prese nte d as fille d i n t he 
e C R F at t he ti me of t he data e x p ort.
H a n dli n g of missi n g d at a:
F or i de ntif icati o n of A E treat me nt e mer ge nce, i nc o m pletes dates will be ha n dle d as f oll o ws:

I n case t he o nset date is c o m pletel y missi n g or t he o nset is i n t he sa me ye ar (if t he o nset 
ye ar is a vaila ble o nl y) or t he o nset is i n t he sa me m o nt h a n d y ear (if t he da y is missi n g) as 
start of trial treat me nt t he n t he o nset date will be re place d b y  the mi ni m u m of start trial 
treat me nt a n d A E res ol uti o n date.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI






M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 /6 0

N u m ber of scree ne d s u bjects *

N u m ber of s u bjects disc o nti n ue d pri or treat me nt start ( o verall a n d b y reas o n) *

N u m ber of s u bjects w h o c o nti n ue d be y o n d scree ni n g

N u m ber of s u bjects w h o c o m plete d treat me nt wit h M 3 8 1 4 (“ M S C 2 4 9 0 4 8 4 A Ter mi nati o n” 
e C R F pa ge)

N u m ber of s u bjects w h o c o m plete d treat me nt wit h R T (“ Ra di ot hera py T er mi nati o n” e C R F 
pa ge)

N u m ber of s u bjects w h o c o m plete d treat me nt wit h Cis plati n (“ Cis plati n Ter mi nati o n” 
e C R F pa ge)

N u m ber of s u bjects disc o nti n ue d fr o m M 3 8 1 4 o verall a n d b y  reas o n (“ M S C 2 4 9 0 4 8 4 A 
Ter mi nati o n” e C R F pa ge)

N u m ber 
of s u bjects disc o nti n ue d fr o m R T o verall a n d b y  reas o n (“ Ra di ot hera py 
Ter mi nati o n” e C R F pa ge)

N u m ber of s u bjects disc o nti n ue d fr o m Cis plati n o verall a n d b y  reas o n (“ Cis plati n 
Ter mi nati o n” e C R F pa ge)

N u m ber of s u bjects w h o c o m plete d t he trial (“ St u d y  Ter mi nati o n” e C R F pa ge).

N u m ber of s u bjects disc o nti n ue d fr o m trial o verall a n d b y  reas o n (“ St u d y Ter mi nati o n” 
e C R F pa ge).

N u m ber of s u bjects i n f oll o w- u p. A n d f or t h ose, t he n u m ber of s u bjects last k n o w n ali ve 
wit hi n 3 m o nt hs bef ore c ut-off date a n d n u m ber of s u bjects last k n o w ali ve m ore t ha n 3 
m o nt h pri or t o c ut- off date
* T hese will be re p orte d i n t he o verall c ol u m n o nl y .
A sec o n d s u m mar y  ta ble o n a nal ys is sets will be ge nerate d:

N u m ber of s u bjects i n Scree ne d P o p ulati o n

N u m ber of s u bjects i n S A F A nal ys is Set ( O verall a n d per d ose le vel)

N u m ber of s u bjects i n F A S A nal y sis Set ( O verall a n d per d ose le vel)

N u m ber of s u bjects i n D E A nal y sis Set ( O verall a n d per d ose le vel)

N u m ber of s u bjects i n B M K A nal ys is Set ( O verall a n d per d ose le vel)

N u m ber of s u bjects i n P K A nal ys is Set ( O verall a n d per d ose le vel)
A t hir d s u m mar y ta ble will dis pla y  the n u m ber of s u bjects o verall, i n eac h c o u ntr y a n d i n eac h site 
( per A nal ysis Set).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 /6 0
A listi n g of s u bject dis p ositi o n will i ncl u de t he f oll o wi n g i nf or mati o n (as a p plica ble): F or m ulati o n, 
d ose le vel, s u bject i de ntificati o n n u m ber, date of I nf or me d C o nse nt F or m (IC F), E nr olle d 
p o p ulati o n, reas o n f or scree n fail ure, date of first a n d last d ose, F A S/ S A F a nal ysis set, D E a nal ysis 
set, B M K a nalys is set a n d P K a nal ysis set.
A sec o n d listi n g will i ncl u de t he f oll o wi n g trial disc o nti n uati o n i nf or mati o n: F or m ulati o n, d ose 
le vel, s u bject i de ntificati o n n u m ber, e n d of trial stat us (c o m plete d, o n g oi n g, disc o nti n ue d), t he 
reas o n f or trial disc o nti n uati o n, t he date of trial ter mi nati o n, ti me o n trial (ti me fr o m IC F si g nat ure 
t o e n d of trial), a n d t he date of first a n d last d ose of M 3 8 14 a n d R T.
A t hir d listi n g will i ncl u de t he f oll o wi n g M 3 8 1 4 disc o nti n uati o n i nf or mati o n: F or m ulati o n, d ose 
le vel, s u bject i de ntificati o n n u m ber, e n d of treat me nt stat us (c o m plete d, o n g oi n g, disc o nti n ue d), 
t he reas o n f or M 3 8 1 4 disc o nti n uati o n, a n d t he date of first a n d last d ose.
A f o urt h listi n g will i ncl u de t he f oll o wi n g R T disc o nti n uati o n i nf or mati o n: F or m ulati o n, d ose 
le vel, s u bject i de ntificati o n n u m ber, e n d of treat me nt stat us (c o m plete d, o n g oi n g, disc o nti n ue d), 
t he reas o n f or R T disc o nti n uati o n a n d t he date of first a n d last d ose.
F or ar m B a listi n g will i ncl u de t he f oll o wi n g Cis plati n disc o nti n uati o n i nf or mati o n: F or m ulati o n, 
d ose le vel, s u bject i de ntificati o n n u m ber, e n d of treat me nt stat us (c o m plete d, o n g oi n g, 
disc o nti n ue d), t he reas o n f or Cis plati n disc o nti n uati o n, a n d t he date of first a n d last d ose.
I n a d diti o n, for t he assess me nt of C O VI D- 1 9 i m pact o n t his st u d y, a listi n g will i ncl u de t he 
f oll o wi n g i nf or mati o n (as a p plica ble): F or m ulati o n, d ose le vel, s u bject i de ntificati o n n u m ber, date 
of first a n d last d ose, pa n de mic start date i n t he c o u ntr y, if D L T or a n y F U P peri o ds were 
p ote ntiall y  affecte d b y  pa n de mic, if a n y C O VI D - 1 9 relate d A E or P D occ urre d d uri n g t he 
pa n de mic peri o d .
1 0. 2
Pr ot oc ol De vi ati o ns
1 0. 2. 1
I m p ort a nt Pr ot oc ol De vi ati o ns
T he f oll o wi n g listin gs of i m p orta nt pr ot oc ol de viati o ns will be pr o vi de d o n t he safet y p o p ulati o n,
i ncl u di n g:

I m p orta nt pr ot oc ol de viati o n s i de ntifie d b y  me dical 
re vie w, i ncl u di n g pr o hi bite d 
me dicati o ns. I m p orta nt pr ot oc ol de viati o ns will be re vie we d a n d a gree d u p o n i n t he D ata 
Re vie w Meeti n g.
T his listi n g will i ncl u de: f or m ulati o n, d ose le vel, s u bject i de ntifier, 
de viati o n cate g or y,de viati o n descri pti o n as dis pla ye d i n C T M S a n d if t he P D occ urre d after 
pa n de mic start.

De viati o ns fr o m i ncl usi o n or e xcl usi o n criteria, usi n g i nf or mati o n pr o vi de d i n “ St u d y 
E ntr y ” e C R F pa ge . T his listi n g will i ncl u de: f or m ulati o n, d ose le vel, s u bject i de ntifier, 
i ncl usi o n/e xcl usi o n criteria n ot met.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 /6 0
I n a d diti o n, de viati o n fr o m treat me nt c o m plia nce, ie. patie nts w h o recei ve d less t ha n 8 0 % of 
pla n ne d d ose will be liste d. T his listi n g will i ncl u de: f or m ulati o n, d ose le vel, s u bject i de ntifier, 
M 3 8 1 4 c o m plia nce ( %), R T c o m plia nce ( %), M 3 8 1 4 first a n d last d ose date, R T first a n d last d ose 
date.
A s u bject listi n g of a n y C O VI D -1 9 relate d P D will als o be pr o vi de d.
1 0. 2. 2
Re as o ns Le a di n g t o t he E xcl usi o n fr o m a n A n al ysis Set
F or s u bjects e xcl u de d fr o m t he d ose escalati o n a nal ysis set, t he reas o ns f or excl usi o n will be liste d. 
T he listi n g will i ncl u de: f or m ulati o n, d ose le vel, s u bject i de ntifier a n d t he reas o n f or e xl usi o n.
1 1
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics
P o p ul ati o n: S A F A n alysis Set
All de m o gra p hics a n d baseli ne c haracteristics wil l be liste d a n d s u m marize d b y  dose le vel a n d 
o verall usi n g S A F A nal ysis set.
1 1. 1
De m o gr a p hics
T he f oll o wi n g de m o gra p hic c haracteristics will be s u m marize d usi n g t he i nf or mati o n fr o m t he 
“ De m o gra p hics” e C R F pa ges.

Se x: male, fe male

Race: W hite, Blac k of Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n or ot her Pacific Isla n der, N ot c ollecte d at t his s ite, Ot her

Et h nicit y : His pa nic or Lati n o, N ot His pa nic or Lati n o

A ge ( y ears)

A ge cate g ories :
o
< 6 5 y ears, ≥ 6 5 y ears
o
6 5 - 7 4, 7 5- 8 4, ≥8 5
S pecificati o ns f or c o m p utati o n:

A ge [ y ears]: 
( date of gi ve n i nf or me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 /6 0
N ote: Tec h nicall y i n case t he da y or m o nt h is n ot k n o w n fr o m at least o ne of t he dates, 
t he da y  (d a y  an d m o nt h  in case t he m o nt h is missi n g) of b ot h dates, t he date of birt h 
a n d t he date of i nf or me d c o nse nt, will be set t o 1 a n d t he f or m ula gi ve n a b o ve will be 
a p plie d.
Data will als o be pr o vi de d i n listi n gs (see secti o n 1 1. 3 ).
1 1. 2
Me dic al Hist or y
P o p ul ati o n: S A F a n alysis set
T he me dical hist or y  will be s u m marize d fr o m t he “ Me dical Hist or y ” e C R F pa ge, usi n g t he m ost 
rece nt a vaila ble versi o n of Me d D R A ( versi o n 1 9. 1 or later) preferre d ter m ( P T) as e ve nt cate g or y 
a n d Me d D R A s ys te m or ga n class ( S O C) b o dy ter m as B o d y S ys te m cate g or y.
Me dical hist or y  will be dis pla y e d i n ter ms of fre q ue nc y ta bles: or dere d b y  pri mar y SO C a n d P T 
i n al p ha betic or der.
A s u p p orti ve listi n g of Me dical Hist or y  d at a b y su bject will i ncl u de all t he rele va nt data fiel ds as 
c ollecte d o n t he “ Me dical Hist or y ” eC R F pa ges.
1 1. 3
Ot her B aseli ne C h ar acteristics
P o p ul ati o n: S A F a n alysis set
T he f oll o wi n g baseli ne c haracteristics will be s u m marize d usi n g t he i nf or mati o n fr o m t he “ Vital 
Si g ns” a n d “ E C O G perf or ma nce stat us” e C R F pa ges.

Hei g ht (c m)

Wei g ht ( k g)

B S A ( m²) = ([ Heig ht(c m) × Wei g ht( k g)]/ 3 6 0 0) ½

E C O G Perf or ma nce stat us
A listi n g of baseli ne c haracteristics will i ncl u de t he f oll o wi n g i nf or mati o n (as a p plica ble): 
F or m ulati o n, d ose le vel, s u bject i de ntificati o n n u m ber, date of birt h, a ge ( years), se x, race, 
hei g ht (c m), wei g ht ( k g), E C O G perf or ma nce stat us, all res ults fr o m ser ol o g y test a n d res ult fr o m 
pre g na nc y  test (ser u m β-H C G). 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 /6 0
I nf or mati o n o n disease c haracteristics c ollecte d o n t he “ Disease Hist or y” e C R F pa ge will be 
s u m marize d as f oll o ws:

Site of pri mar y  t u m or: o nl y n o n missi n g cate g ories will be dis pla ye d

T u m or hist o pat h ol o gic / c y t ol o gic ty pe : all cate g ories fr o m e C R F will be descri be d

T u m or hist o pat h ol o gic / c y t ol o gic ty p e gra de : fr o m G X t o G 4

Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs)

Ti me si nc e d oc u me nte d, l ocall y a d va nce d, i n o pera ble or metastatic disease dia g n osis ( m o nt hs)

Ti me si nce last pr o gressi o n of disease pri or t o st u d y e ntr y ( m o nt hs)

T N M classificati o n at i nitial dia g n osis : eac h T, N, M cate g or y will be descri be d ( T X, T 0, N 1, 
etc.)

T N M classificati o n at st u d y e ntr y: eac h T, N, M cate g or y will be descri be d ( T X, T 0, N 1, etc.)
I n a d diti o n, a listi n g of disease hist or y will be pr o vi de d i ncl u di n g all rele va nt data.
F or Ar m B, a listi n g i ncl u di n g H P V stat us i n t u m or a n d a listi n g i ncl u di n g a u di o gra m res ults will 
be pr o vi de d base d o n date fr o m t he “ H P V stat us” e C R F pa ge a n d “ A u di o gra m” e C R F pa ge 
res pecti vely.
1 2
P re vi o us or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures
P o p ul ati o n: S A F A n alysis Set
1 2. 1
Pri or A nti -C a ncer Tre at me nts a n d pr oce d ures
T he pri or a nti-ca ncer treat me nts a n d pr oce d ures are c ollecte d u n der t he “ Pri or a nti-ca ncer dr u g 
t hera pies”, “Pri or a nti -ca ncer s ur geries”, a n d “ Pri or a nti -ca ncer ra di ot hera p y” e C R F pa ges .
T he listi n gs of pri or a nti -ca ncer treat me nts a n d p r oce d ures will be pr o vi de d: 
Listi n g of pri or a nti- ca ncer dr u g t hera pies, 
L isti n g of pri or s ur geries,
L isti n g of pri or ra di ot hera p y. 
T hese will i ncl u de t he s u bject i de ntificati o n n u m ber, f or m ulati o n, d ose le vel a n d all t he rele va nt 
c ollecte d data -fiel ds o n t he c orres p o n di n g e C R F pa ges.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 /6 0
1 2. 2
Pre vi o us Me dic ati o ns
Pre vi o us me dicati o ns are me dicati o ns, ot her t ha n trial me dicati o ns a n d pre -me dicati o ns f or trial 
dr u g, w hic h are ta ke n a n d st o p pe d bef ore first a d mi nistrati o n of trial treat me nt. 
Pre vi o us me dicati o ns
will be s u m marize d fr o m t he “ Rele va nt pre vi o us me dicati o ns” 
a n d 
“C o nc o mita nt me dicati o ns ” e C R F pa ges. T he A nat o mical T hera pe utic C he mical (A T C )- 2n d le vel 
a n d P T will be ta b ulate d as gi ve n fr o m t he W orl d Healt h Or g a nizati o n Dr u g Dicti o nar y  (m ost 
rece nt a vaila ble versi o n of W H O -D D , Se pt. 2 0 1 6 or later). If m ulti ple A T C ca n be assi g ne d t o a 
dr u g, all A T Cs will be re p orte d.
I n case t he date val ues will n ot all o w t o u ne q ui v ocall y  all ocate a me dicati o n t o pre vi o us
me dica ti o n, t he me dicati o n will be c o nsi dere d as pre vi o us me dicati o n (see secti o n 9 f or i nc o m plete 
or missi n g dates) .
Pre vi o us me dicati o ns will als o be liste d. T he listi n g will i ncl u de: s u bject i de ntificati o n n u m ber, 
f or m ulati o n, d ose le vel a n d all c orres p o n di n g c ollecte d data -fiel ds o n t he c orres p o n di n g e C R F 
pa ge.
1 2. 3
C o nc o mit a nt Me dic ati o ns
C o nc o mita nt treat me nts are me dicati o ns, ot her t ha n trial me dicati o ns, w hic h are ta ke n b y s u bjects 
a n y ti me o n- trial ( o n or after t he first d a y  of st u d y treat me nt f or eac h s u bject) or wit hi n 3 0 d a y s 
f or Ar m A a n d 3 5 d a y s f or Ar m B after last d ose of trial treat me nt. Me dicati o ns starte d after 3 0 
(res p. 3 5) d a y s will be prese nte d a n d fla g ge d in listi n gs b ut will n ot be ta ke n i nt o acc o u nt i n 
s u m mar y ta bles.
C o nc o mita nt me dicati o ns will be s u m marize d fr o m t he “ C o nc o mita nt me dicati o n s” e C R F pa ge . 
T he A T C - 2n d le vel a n d P T will be ta b ulate d as gi ve n fr o m t he m ost rece nt a vaila ble versi o n of 
W H O -D D, Se pt. 2 0 1 6 or later. If m ulti ple A T C ca n be assi g ne d t o a dr u g, all A T Cs will be 
re p orte d.
I n case t he date val ues will n ot all o w t o u ne q ui v ocall y  all ocate a me dicati o n t o c o nc o mita nt 
me dicati o n, t he me dicati o n will be c o nsi dere d as c o nc o mita nt me dicati o n
(see secti o n 9 f or 
i nc o m plete or missi n g dates).
C o nc o mita nt me dicati o ns will als o be liste d. T he listi n g will i ncl u de: s u bject i de ntificati o n 
n u m ber, f or m ulati o n, d ose le vel a n d all c orres p o n di n g c ollecte d data -fiel ds o n t he c orres p o n di n g 
e C R F pa ge.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 /6 0
1 2. 4
C o nc o mit a nt Pr oce d ures
C o nc o mita nt pr oce d ures are pr oce d ures w hic h are u n derta ke n a n y ti me o n - trial or wit hi n 3 0 da ys
f or Ar m A a n d 3 5 da ys f or Ar m B after last d ose of trial treat me nt. T hese will be liste d acc or di n g 
t o t he C R F pa ge “ C o nc o mita nt Pr oce d ures” . Pr oce d ures starte d after 3 0 (res p. 3 5) d a y s will be 
prese nte d a n d fla g ge d i n listi n g .
I n case t he date val ues will n ot all o w t o u ne q ui v ocall y all ocat e a pr oce d ure t o c o nc o mita nt
pr oce d ure , t he pr oce d ure will be c o nsi dere d as c o nc o mita nt pr oce d ure (see secti o n 9 f or 
i nc o m plete or missi n g dates).
T he listi n g will 
i ncl u de: s u bject i dentificati o n n u m ber, f or m ulati o n, d ose le vel a n d all 
c orres p o n di n g c ollecte d data- fiel ds o n t he c orres p o n di n g e C R F pa ge.
1 2. 5
A nti -c a ncer p ost-tre at me nt
A nti- ca ncer p ost -treat me nts will be liste d acc or di n g t o e C R F pa ge “ A nti- ca ncer treat me nt after 
disc o nti n uati o n ”. T he listi n g will i ncl u de: s u bject i de ntificati o n n u m ber, f or m ulati o n, d ose le vel 
a n d all c orres p o n di n g c ollecte d data -fiel ds o n t he c orres p o n di n g e C R F pa ge.
A nti- ca ncer p ost -s ur geries a n d p ost -ra di ot hera pies will als o be liste d acc or di n g t o e C R F pa ges 
“ A nti-ca ncer 
s ur geries 
after 
disc o nti n uati o n” 
a n d 
“ A nti-ca ncer 
ra di ot hera py 
after 
disc o nti n uati o n”.
1 3
Tre at me nt C o m pli a nce a n d E x p os ure
P o p ul ati o n: S A F A n alysis Set
Treat me nt c o m plia nce a n d e x p os ure will be liste d a n d s u m marize d b y  dose le vel a n d o verall usi n g 
S A F A nal ys is set.
All d osi n g calc ulati o ns a n d s u m maries will be base d o n “ M S C 2 4 9 0 4 8 4 A A d mi nistrati o n” ,
“ Ra di ot hera p y A d mi nistrati o n” a n d “ Cis plati n A d mi nistrati o n” e C R F pa ges.
I n P hase Ia, s u bjects will recei ve treat me nt wit h M 3 8 1 4 at a starti n g d ose of 1 0 0 m g Q D f or Ar m 
A a n d 5 0 m g Q D f or Ar m B , w hic h will be gi ve n 1. 5 h o urs bef ore eac h R T fracti o n ( 3 G y) f or u p 
t o 1 0 fracti o ns ( Ar m A) or 2 Gy f or 3 3 t o 3 5 fracti o ns ( Ar m B) . I n a d diti o n, i n Ar m B, o n Fracti o n 
D a y s 1 a n d 3 1 f or t he 1 0 0 m g/ m 2 d ose, or wee kl y f or t he 4 0 m g/ m 2 d ose, cis plati n will be gi ve n 
after oral i nta ke of M 3 8 1 4 a n d bef ore R T is starte d. D ose escalati o n will c o nti n ue u p t o a ma xi m u m 
d ose of M 3 8 1 4 8 0 0 m g/ da y .
N u m ber of tre at me nt a d mi nistr ati o ns
T he n u m ber of fracti o n da y s of treat me nt will be s u m marize d f or Ra di ot hera p y b y d ose le vel a n d 
o verall.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI






M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 /6 0
I n a d diti o n, a listi n g of acc o u nta bilit y for M 3 8 1 4 
acc or di n g t o pa ge “ M 3 8 1 4/ Place b o 
acc o u nta bilit y” of e C R F will be pr o d uce d . T his listi n g will i ncl u de t he s u bject i de ntificati o n 
n u m ber, a n d all c ollecte d fiel ds of t he c orres p o n di n g e C R F Pa ge. 
1 4
Effic ac y A n al yses
Sec o n dar y  efficac y en d p oi nts i ncl u de Best O verall Res p o nse ( B O R) a n d t u m or meas ure me nts. 
T u m or assess me nts are base d o n l ocal e val uati o ns b y  the i n vesti gat or acc or di n g t o R E CI S T 1. 1 
criteria. L ocal e val uati o ns of tar get, n o n -tar get a n d ne w lesi o ns are use d t o deri ve t he B O R.
1 4. 1
Best O ver all Res p o nse
P o p ul ati o n: F A S A n alysis Set
T he Best O verall Res p o nse ( B O R) will be defi ne d as t he best res p o nse per R E CI S T 1. 1 acr oss all 
ti me p oi nts u ntil deter mi nati o n of Pr o gressi ve Disease ( P D) or c ut -off date , usi n g t he I n vesti gat or 
re p orte d o verall res p o nse per ti me p oi nt a n d e xcl u di n g assess me nts after t u m or s ur ger y .
B O R will be defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or exa m ple, a s u bject w h o has 
sta ble disease (S D ) at t he first assess me nt, partial res p o nse (P R ) at t he sec o n d assess me nt, a n d P D 
at t he last assess me nt has a B O R of P R) . T he or der t o o btai n t he B O R is t he f oll o wi n g : c o m plete 
res p o nse ( C R), Partial Res p o nse ( P R), Sta ble Disease ( S D), Pr o gressi ve Disease ( P D), N ot 
E val ua ble ( N E).
W he n S D is belie ve d t o be t he best res p o nse, it m ust als o meet t he pr ot oc ol -s pecifie d mi ni m u m
6 wee ks ( 4 2 d a y s) fr o m first da y  of treat me nt. If t he mi ni m u m ti me is n ot met, t he s u bject’s best 
o verall res p o nse de pe n ds o n t he s u bse q ue nt assess me nts. F or e xa m ple, a s u bject w h o has S D at
t he first assess me nt, P D at t he sec o n d assess me nt a n d d oes n ot meet t he mi ni m u m d urati o n f or S D, 
will ha ve a best o verall res p o nse of P D. T he sa me su bject l ost t o f oll o w- u p after t he first S D 
assess me nt w o ul d be c o nsi dere d N E f or B O R.
If a s u bject has missi n g baseli ne t u m or assess me nt a n d/ or n o t u m or assess me nt o n- treat me nt, B O R 
will be N E .
T he c o nfir me d B O R will be als o a nal yze d. I n t his case, C R a n d P R nee d t o be c o nfir me d at a 
s u bse q ue nt assess me nt, at least 4 wee ks after i nitial o verall res p o nse assess me nt of C R/ P R.
C o nfir me d B O R will be deri ve d as descri be d i n R E CI S T 1. 1 g ui da nce.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 /6 0
O verall 
res p o nse first 
ti me p oi nt
O verall res p o nse 
s u bse q ue nt ti me
p oi nt *
C o nfir me d B O R
C R
C R
C R
C R
P R
S D, P D or P R a
C R
S D
S D, if mi ni m u m criteria f or S D d urati o n met at first ti me p oi nt . 
O t her wise P D
C R
P D
S D, if mi ni m u m criteria f or S D d urati o n met at first ti me p oi nt . 
O t her wise P D
C R
N E
S D, if mi ni m u m criteria f or S D d urati o n met at first ti me p oi nt . 
O t her wise N E
P R
C R
P R
P R
P R
P R
P R
S D
S D
P R
P D
S D, if mi ni m u m criteria f or S D d urati o n met. O t her wise P D
P R
N E
S D, if mi ni m u m criteria f or S D d urati o n met. O t her wise N E
N E
N E
N E
* S u bse q ue nt ti me p oi nt is n ot necessaril y t he direct s u bse q ue nt sca n (e g. P R-S D - P R will ha ve P R as c o nfir me d B O R)
a If a C R is tr ul y met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease meeti n g P R criteri a
relati ve t o baseli ne, ma kes t he disease P D at t hat p oi nt (si nce disease m ust ha ve rea p peare d after C R). Best res p o nse w o ul d
de pe n d o n w het her mi ni m u m d urati o n f or S D was met. H o we ver, s o meti mes ‘ C R’ ma y be clai me d w he n s u bse q ue nt sca ns
s u g gest s mall lesi o ns were li kel y still prese nt a n d i n fact t he patie nt ha d P R, n ot C R at t he first ti me p oi nt. U n der t hese
circ u msta nces, t he ori gi nal C R s h o ul d be c ha n ge d t o P R a n d t he best res p o nse is P R.
T o a nal yze t u m or res p o nse, it ma y  be necessar y t o deter mi ne t he date of t u m or assess me nt, e. g. t o 
c hec k w het her S D was asserte d after a s uita ble ti me li mit after baseli ne. I n case of differe nt dates 
of sca ns wit hi n t he sa me t u m or assess me nt, t he earliest sca n date is use d as t he date of t u m or 
assess me nt.
B ot h C o nfir me d a n d U nc o nfir me d B O R will be s u m marize d b y  ta b ulati n g t he n u m ber a n d 
perce nta ge of s u bjects wit h C R, P R, S D, P D or N E as B O R. I n a d diti o n, c o nfir me d o bjecti ve 
res p o nse (c o nfir me d B O R of C R or P R), u nc o nfir me d o bjecti ve res p o nse ( u nc o nfir me d B O R of 
C R or P R a n d disease c o ntr ol will be s u m marize d. O bjecti ve res p o nse rate ( O R R) a n d disease 
c o ntr ol rate ( D C R) are i n dicate d t o get her wit h e xact Cl o p per -Pears o n 9 5 %- c o nfi de nce i nter vals
( Cl o p per & Pears o n, 1 9 3 4).
T he listi n g of t u m or assess me nts (i ncl u di n g e. g. lesi o n n u m ber, descri pti o n a n d site, t ype of lesi o n, 
i ma gi n g date, assess me nt met h o d, dia m eter ( m m), s u m of dia meter of tar get lesi o ns, B O R 
(c o nfir me d a n d u nc o nfir me d) will be pr o vi de d b y s u bject as rec or de d fr o m t he “ Tar get Lesi o ns”, 
“ S u m of Dia meters”, “ N o n-Tar get Lesi o ns” , “ Ne w Lesi o ns” a n d “ Assess me nt of disease base d o n 
i ma gi n g” e C R F pa ges.
A s pi der pl ot will dis pla y  the perce nta ge c ha n ge fr o m baseli ne i n s u m of l o n gest dia meter of tar get 
lesi o n a gai nst t he date f or eac h s u bject.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 /6 0
A s wi m mer pl ot dis pla yi n g s o me ke y ra di ol o gical milest o nes will be pr o d uc e d f or eac h d ose le vel 
se paratel y. F or eac h s u bject, t he ti me fr o m treat me nt start u ntil e n d of f oll o w- u p will be 
re prese nte d (fr o m treat me nt start t o last date k n o w n t o be ali ve or date of deat h). I n a d diti o n, 
f oll o wi n g i nf or mati o n will be dis pla y e d: ti me t o best o verall u nc o nfir me d res p o nse ( C R, P R or 
S D), ti me t o pr o gressi o n a n d stat us at t he e n d of t he f oll o w -u p (ali ve or dea d). 
F or s u bjects ali ve, t he f oll o wi n g dates will be use d t o deter mi ne t he last date k n o w n t o be ali ve 
pri or or at data c ut -off.

All patie nt assess me nt dates:
o
La b orat or y  assess me nts usi n g i nf or mati o n fr o m “ Ser ol o g y”, “ He mat ol o g y”, 
“ Bi oc he mistr y”, “ C oa g ulati o n”, “ Uri nal ys is”, “ Micr osc o pic a nal ysis”, “ Pre g na nc y 
test” a n d “ Platelet a g gre gati o n e val uati o n” e C R F pa ges ( L B D T C varia ble fro m L B 
S D T M d o mai n t o be use d) 
o
V ital si g ns usi n g i nf or mati o n fr o m “ Vital si g ns” e C R F pa ge ( V S D T C varia ble fr o m 
V S S D T M d o mai n t o be use d)
o
Perf or ma nce stat us usi n g “ E C O G Perf or ma nce stat us” e C R F pa ge ( Q S D T C 
varia ble fr o m Q S S D T M d o mai n t o be use d)
o
E C G, usi n g i nf or mati o n fr o m “ Tri plicate 1 2- lea d electr ocar di o gra m” ( E G D T C 
varia ble fr o m E G S D T M d o mai n t o be use d)
o
T u m or assess me nts usi n g “ T u m or assess me nts” e C R F pa ges ( T R D T C/ T U D T C
varia ble fr o m T R / T U S D T M d o mai n t o be use d)
o
St u d y  mai nte na nce assess me nts ( X X D T C varia ble fr o m X X S D T M d o mai n t o be 
use d)

Start a n d e n d dates of c o nc o mita nt me dicati o ns or a nti-ca ncer t hera pies a d mi nistere d after 
st u d y treat me nt disc o nti n uati o n usi n g “ C o nc o mita nt me dicati o ns”, “ A nti-ca ncer treat me nt 
after disc o nti n uati o n details” e C R F pa ge s ( C M S T D T C a n d C M E N D T C varia ble fr o m C M 
S D T M d o mai n t o be use d)

A E start a n d e n d dates usi n g “ A d verse e ve nts details” e C R F pa ge ( A E S T D T C a n d 
A E E N D T C varia bles fr o m A E S D T M d o mai n t o be use d)

St u d y  treat me nt
a d mi nistrati o n
dates 
usi n g 
“ M S C A 2 4 9 0 4 8 4 A 
A d mi nistrati o n” , 
“ Ra di ot hera p y A d mi nistrati o n” a n d “ Cis plati n A d mi nistrati o n” e C R F pa ge s ( E X S T D T C 
varia ble fr o m E X S D T M d o mai n t o be use d)

Macr osc o pic 
si g ns of blee di n g usi n g “ Macr osc o pics si g ns of blee di n g” e C R F pa ge 
( C E D T C or F A D T C fr o m C E/ F A S D T M d o mai ns)

S ur vi val f oll o w- u p dates usi n g “ S ur vi val F oll o w - u p pa ge” ( Y F S T D T C varia ble fr o m Y F 
S D T M d o mai n w here Y F T E S T C D =” S U R V S T A T”).
I n a d diti o n, waterfall pl ot re prese nti n g t he best perce nta ge c ha n ge i n t u m or size fr o m baseli ne per 
s u bject will be pr o vi de d. T he u nc o nfir me d B O R will als o be prese nte d as a n a n n otati o n o n eac h 
vertical bar.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 /6 0
1 5
S afet y A n al yses
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y en d p oi nts t hat are 
c o m m o n acr oss cli nical trials s uc h as a d verse e ve nts, la b orat or y tests a n d vital si g ns.
T he pri mar y  en d p oi nt of t he P hase Ia is t he occ urre nce of a D L T f or a s u bject d uri n g t he D L T 
o bser vati o n peri o d ( 5 wee ks after t he start of R T f or Ar m A a n d 1 2 wee ks after t he start of R T f or 
Ar m B ). Base d o n t he data o bser ve d, a rec o m me n dati o n of t he ne xt d ose le vel is base d o n a 
Ba yesia n d ose escalati o n desi g n usi n g a t w o-para metric l o gistic re gressi o n m o del. M ore details 
a b o ut t he a nalys is t o be pr o vi de d t o S M C me m bers are prese nte d i n a de dicate d I A P.
1 5. 1
D L T ( Pri m ar y e n d p oi nt)
P o p u l ati o n: D E A n alysis Set
A ta ble wit h a s u m mar y D L Ts d uri n g t he D L T peri o d , as c o nfir me d b y  the S M C, will be pr o vi de d 
f or eac h d ose le vel a n d o verall wit h:
N u m ber of s u bjects wit h n o D L T 
N u m ber of s u bjects wit h D L T: o ne D L T, at least t w o D L Ts
T he listi n g of all D L Ts (i de ntifie d eit her by I n vesti gat or or b y S M C) will als o be pr o vi de d.
1 5. 2
A d verse E ve nts
All T E A Es will be s u m marize d, i.e. t h ose e ve nts t hat are e mer ge nt d uri n g treat me nt ha vi n g bee n 
a bse nt pre -treat me nt, or w orse n relati ve t o t he pr e -treat me nt state a n d wit h o nset dates occ urri n g 
wit hi n t he first d osi n g da y  of trial treat me nt u ntil 3 0 d a ys after t he last d ose of trial treat me nt. If 
a n a d verse e ve nt starte d bef ore treat me nt start a n d i m pr ove d d uri n g treat me nt (i.e. wit h t he sa me 
P T direc tl y foll o wi n g, b ut l o wer gra de) it s h o ul d n ot be c o u nte d as a T E A E. H o we ver, if a n a d verse 
e ve nt starte d eit her bef ore or d uri n g t he treat me nt peri o d a n d w orse ne d d uri n g t he treat me nt peri o d 
t his s h o ul d be re p orte d as a T E A E.
C o u nti n g r ules a n d o bser vati o n peri o ds f or A Es d uri n g t he treat me nt peri o d ( T E A Es ):
T he treat me nt peri o d is defi ne d fr o m t he first d osin g da y of trial treat me nt u ntil 3 0 da y s after t he 
last d ose of trial treat me nt or t he cli nical c ut-off date.
If a n A E is re p orte d f or a gi ve n s u bject m ore t ha n o nce d uri n g treat me nt, t he w orst se verit y a n d 
t he w orst relati o ns hi p t o trial treat me nt will be ta b ulate d.
A d verse e ve nts relate d t o trial treat me nt are t h ose e ve nts wit h relati o ns hi p missi n g, u n k n o w n or 
relate d t o at least o ne treat me nt ( M 3 8 1 4, R T or Cis plati n ).
A d verse e ve nts relate d t o M 3 8 1 4 are t h ose e ve nts relate d t o M 3 8 1 4, re gar dless t o relati o ns hi p 
wit h R T a n d/ or Cis plati n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 /6 0
A d verse e ve nts relate d t o R T are t h ose e ve nts relate d t o R T, re gar dless t o relati o ns hi p wit h 
M 3 8 1 4 a n d/ or Cis plati n
A d verse e ve nts relate d t o Cis plati n are t h ose e ve nts relate d t o M 3 8 1 4, re gar dless t o relati o ns hi p 
wit h M 3 8 1 4 a n d/ or R T
I n case a s u bject has e ve nts wit h missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he n o n-
missi n g gra des wi ll be dis pla ye d.
F or i de ntificati o n of A E treat me nt e mer ge nce, i nc o m plete dates will be ha n dle d usi n g t he r ules 
prese nte d i n secti o n 9 .
A Es will be c o de d acc or di n g t o t he c urre nt Me d D R A. T he se verity of A Es w ill be gra de d usi n g 
Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI-C T C A E) 
versi o n 4. 0 3 t o xicit y gra des. 
1 5. 2. 1
All A d verse E ve nts
P o p ul ati o n: S A F a n alysis set
A d verse e ve nts will be s u m marize d b y  worst se verit y (acc or di n g t o N CI -C T C A E versi o n 4. 0 3) 
per s u bject, usi n g t he m ost rece nt a vaila ble Me d D R A versi o n ( 1 9. 1 or later) P T as e ve nt cate g or y 
a n d pri mar y S O C b o d y ter m as B o dy S ys te m cate g or y. 
Fre q ue nc y  ta bles f or A Es ca pt ure d o n t he “ A d ve rse E ve nts” e C R F pa ges will be base d o n T E A Es , 
i.e. t h ose e ve nts wit h o nset dates occ urri n g wit hi n t he treat me nt peri o ds (as defi ne d a b o ve).
A first o ver vie w ta ble of a d verse e ve nts will be pr o vi de d b y  dose le vel a n d o verall b y  su m marizi n g 
t he n u m ber a n d perce nta ge of patie nts wit h a n y :

T E A E

T E A Es relate d t o trial treat me nt, (i.e. M 3 8 1 4, R T, or Cis plati n)

T E A Es relate d t o M 3 8 1 4

T E A Es relate d t o R T

T E A Es relate d t o Cis plati n

Seri o us T E A E

Seri o us T E A E relate d t o trial treat me nt, M 3 8 1 4, R T or Cis plati n

T E A Es wit h gra de 3

T E A Es wit h gra de 4

T E A Es wit h gra de 3 relate d t o trial treat me nt, M 3 8 1 4, R T or Cis plati n

T E A Es wit h gra de 4 relate d t o trial treat me nt, M 3 8 1 4, R T or Cis plati n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 /6 0

T E A E lea di n g t o st u d y  disc o nti n uati o n

T E A E lea di n g t o deat h

T E A E lea di n g t o deat h relate d t o trial treat me nt, M 3 8 1 4, R T or Cis plati n
I n a d diti o n, fre q ue nc y ta bles s u m marizi n g e ve nts i n t he f oll o wi n g cate g ories will be pre pare d b y  
d ose le vel a n d o verall, S O C a n d P T i n al p ha betical or der:

T E A Es

T E A Es relate d t o trial treat me nt (i.e., M3 8 1 4, R T , or Cis plati n)

T E A Es relate d t o M 3 8 1 4

T E A Es relate d t o R T

T E A Es relate d t o Cis plati n

Seri o us T E A Es

Seri o us T E A Es relate d t o trial treat me nt

Seri o us T E A Es relate d t o M 3 8 1 4

Seri o us T E A Es relate d t o R T

Seri o us T E A Es relate d t o Cis plat i n

T E A Es b y w orst C T C A E gra de: a n y gr a de (i ncl u di n g A Es wit h missi n g gra de), gra des 3, 
4 a n d 5

T E A Es relate d t o trial treat me nt b y w orst C T C A E gra des : a n y gra de (i ncl u di n g A Es wit h 
missi n g gra de), gra des 3, 4 a n d 5

T E A Es relate d t o M 3 8 1 4
b y w orst C T C A E gra des : a n y gr a de (i ncl u di n g A Es wit h missi n g 
gra de), gra des 3, 4 a n d 5

T E A Es relate d t o R T b y w orst C T C A E gra des : a n y gra de (i ncl u di n g A Es wit h missi n g 
gra de), gra des 3, 4 a n d 5

T E A E relate d t o Cis plati n b y w orst C T C A E gra des : a n y gra de (i ncl u di n g A Es wit h missi n g  
gra de), gra des 3, 4 a n d 5

T E A Es lea di n g t o deat h

T E A Es relate d t o trial treat me nt lea di n g t o deat h

T E A Es relate d t o M 3 8 1 4
lea di n g t o deat h

T E A Es relate d t o R T lea di n g t o deat h

T E A Es relate d t o Cis plati n lea di n g t o deat h
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 /6 0
All ta bles will be s orte d b y al p ha betical or der of S O C a n d P T.
T he listi n g f or all A E s ( w het her treat me nt-e mer ge nt or n ot) will i ncl u de all t he data fiel ds as 
c ollecte d o n t he “ A d verse E ve nt s” e C R F pa ges wit h t he f oll o wi n g ite ms: 

F or m ulati o n

D ose le vel

S u bjec t i de ntificati o n n u m ber, 

First a n d last d ose date 

Re p orte d Ter m wit h S O C a n d P T

Start a n d e n d date wit h t heir c orres p o n di n g treat me nt da y

Treat me nt E mer ge nt A d verse E ve nts fla g ( N/ Y)

Ti mi n g relate d t o treat me nt (if sa me da y  of treat me nt a d mi nistrati o n)

T E A E relate d t o M 3 8 1 4 fla g ( N/ Y)

T E A E relate d t o R T fla g ( N/ Y)

T E A E relate d t o Cis plati n fla g ( N/ Y)

Seri o us A d verse E ve nts fla g ( N/ Y)

D L T fla g ( Y/ N)

C T C A E Gra de

Acti o n ta ke n M 3 8 1 4 , wit h R T a n d wit h Cis plati n

O utc o me of A E

A E occ urre d after C O VI D - 1 9 pa n de mic start (Y/ N ).
C T. g o v / E u dr a C T
S u m mar y  ta bles f or n o n -seri o us a d verse e ve nts e xcl u di n g S A Es a p pl yi n g fre q ue nc y thres h ol d of 
5 % will be pr o vi de d. T he t hres h ol d will be a p plie d o n preferre d ter m usi n g o verall c ol u m n.
E v al u ati o n of C O VI D - 1 9 effects on A Es
T he direct effect of C O VI D -1 9 f or A Es will be assesse d via listi n g of C O VI D -1 9 relate d A Es. T he 
f oll o wi n g listi n g will be ge nerate d usi n g t he ‘ C O VI D-1 9 relate d ter ms Me d D R A 2 3. 0 u p date 
S prea ds heet’, c o nsi deri n g all ‘searc h ter ms f or C O VI D - 1 9-relate d’ =’ Y’. Sa me i nf or mati o n as f or 
t he listi n g of all A Es will be pr o vi de d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 /6 0
1 5. 2. 2
A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n
P o p ul ati o n: S A F a n alysis set
A n o ver vie w ta ble of a d verse e ve nts lea di n g t o disc o nti n uati o n or d ose re d ucti o n will be pr o vi de d 
b y  d ose le vel a n d o verall b y  s u m marizi n g t he n u m ber a n d perce nta ge of patie nts wit h a n y:

T E A E lea di n g t o te m p orar y disc o nti n uati o n of at least o n e trial treat me nt, all trial 
treat me nts, M 3 8 1 4
(re gar dless of ot her trial treat me nts stat us), R T (re gar dless of ot her trial
treat me nts stat us), Cis plati n (re gar dless of ot her trial treat me nts stat us) (c orres p o n di n g t o 
A Es wit h acti o n ta ke n = “ Dr u g i nterr u pte d” f or M S C 2 4 9 0 4 8 4 A
or Cis plati n res pecti vel y 
a n d “D ose s ki p pe d“ f or Ra di ot hera p y)

T E A E lea di n g t o per ma ne nt disc o nti n uati o n of at least o n e trial treat me nt, all trial 
treat me nts, M 3 8 1 4
(re gar dless of ot her trial treat me nts stat us), R T (re gar dless of ot her trial 
treat me nts stat us), Cis plati n (re gar dless of ot her trial treat me nts stat us)
(c orres p o n di n g t o 
A Es wit h acti o n ta ke n = “ Dr u g wit h dra w n” f or M 3 8 1 4 , Ra di ot hera p y
or Cis plati n 
res pecti vely)

T E A E lea di n g t o d ose ti me dela y e d of R T (c orres p o n di n g t o A Es wit h acti o n ta ke n = “D ose 
ti me dela ye d”)
T he f oll o wi n g fre q ue nc y  ta bles will be pr o d uce d f or eac h d ose le vel a n d o verall, b y S O C a n d P T 
i n al p ha betical or der:

T E A Es lea di n g t o te m p orar y disc o nti n uati o n of at least o ne trial treat me nt

T E A Es lea di n g t o te m p orar y disc o nti n uati o n of all trial treat me nts

T E A Es lea di n g t o te m p orar y disc o nti n uati o n of M 3 8 1 4 (re gar dless of ot her trial treat me nts 
stat us)

T E A Es lea di n g t o te m p orar y disc o nti n uati o n of  R T (re gar dless of ot her trial treat me nts 
stat us)

T E A Es lea di n g t o te m p orar y disc o nti n uati o n of  Cis plati n (re gar dless of ot her trial 
treat me nts stat us)

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of at least o ne trial treat me nt

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of all trial treat me nts

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of
M 3 8 1 4
(re gar dless of ot her trial 
treat me nts stat us)

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of  R T (re gar dless of ot her trial treat me nts 
stat us)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 /6 0

T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of  Cis plati n (re gar dless of ot her trial 
treat me nts stat us)

T E A Es lea di n g t o d ose ti me dela ye d of R T
1 5. 2. 3
L ate t o xicities
A n u m b er of o ut p uts will be pr o d uce d f or late a d verse e ve nts. A n a d verse e ve nt is defi ne d as late 
if it starts after t he o n-treat me nt peri o d a n d it meets o ne of t he f oll o wi n g criteria:

It is t he first occ urre nce of a d verse e ve nt f or t his partici pa nt o n Me d D R A pr eferre d ter m 
le vel

It is a rec urri n g a d verse e ve nt b ut t here is ga p bet wee n t he e n d date of t he pre vi o us 
occ ura nce a n d t he start date of t he re-occ ur ence (start date of re occ ure nce – e n d date of 
pre vi o us occ ura nce > 0) 

It is a recc uri n g a d verse e ve nt wit ho ut ga p bet wee n t he e n d date of t he pre vi o us occ ura nce 
a n d t he start date of t he re- occ ur ence a n d t he gra de has w orse ne d :
T he f oll o wi n g will be pr o d uce d f or late t o xcicites:

Ta ble of all late t o xcities b y w orst C T C A E gra des : a n y gra de (i ncl u di n g A Es wit h missi n g 
gra de), gra des 3, 4 a n d 5

Listi n g of all late t o xicities relate d t o M 3 8 1 4

Listi n g of all late t o xicities relate d t o ra di ot hera p y

Listi n g of all late t o xicities gra de 3
   
1 5. 3
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E v e nts
1 5. 3. 1
De at hs
P o p ul ati o n: A L L a n alysis set
All deat hs, deat hs wit hi n 6 0 da y s after first d ose, a n d deat hs wit hi n 3 0 da ys after last d ose of trial
treat me nt, as well as reas o ns f or deat hs , will be ta b ulate d base d o n i nf or mati o n fr o m all rele va nt 
i nf or mati o n a vaila ble i n t he e C R F:
N u m ber of d eat hs
N u m ber of d eat hs wit hi n 6 0 da y s after first d ose of trial treat me nt
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 /6 0
N u m ber of d eat hs wit hi n 3 0 da y s after last d ose of trial treat me nt
Pri mar y  reas o n of d eat h
I n a d diti o n, date a n d ca use of deat h will be pr o vi de d in i n di vi d ual s u bject data listi n gs t o get her 
wit h selecte d d osi n g i nf or mati o n ( date of first / last a d mi nistrati o n, d ose a n d n u m ber of d oses ). 
S u bject listi n g of deat hs i ncl u des c ol u m ns f or:

A Es wit h fatal o utc o me (list P Ts of A Es wit h o utc o me =fatal), 

fla g f or deat h wit hi n 6 0 da y s of first d ose of M 3 8 1 4

fla g f or deat h wit hi n 6 0 da ys of first d ose of R T

fla g f or deat h wit hi n 6 0 da ys of first d ose of Cis plati n

fla g f or deat h wit hi n 3 0 da ys of last d ose of M 3 8 1 4

fla g f or deat h wit hi n 3 0 da ys of last d ose of R T

fla g f or deat h wit hi n 3 0 da ys of last d ose of Cis plati n
1 5. 3. 2
Seri o us A d verse E ve nts
P o p ul ati o n: S A F a n alysis set
S A Es will be s u m marize d f or eac h d ose le vel a n d o verall , b y  S O C, a n d P T i n al p ha betical or der 
(please refer t o Secti o n  1 5. 2. 1 f or ite ms t o be liste d).
I n a d diti o n, s u bject listi n gs of S A Es will be pr o vi de d.
1 5. 3. 3
Ot her Si g nific a nt A d verse E ve nt
N ot a p plica ble.
1 5. 4
Cli nic al L a b or at or y E v al u ati o n
P o p ul ati o n: S A F a n alysis set
L ocal la b orat or y val ues c o n verte d i n sta n dar d u nits (i ncl u di n g c orres p o n di n g n or mal ra n ges) will 
be use d f or t he s u m maries. Val ues bel o w t he detecti o n li mit will be i m p ute d b y  half of t he detecti o n 
li mit.
La b orat or y  res ults will be classi fie d acc or di n g t o t he N CI -C T C A E versi o n 4. 0 3. A d diti o nal 
la b orat or y res ults t hat are n ot part of N C I-C T C A E will be prese nte d acc or di n g t o t he cate g ories: 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI






M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 /6 0
Para meters
Visit
Date ( Treat me nt d a y )
A nal ysis val ue
SI  u nit
C ha n ge fr o m baseli ne
Refere nce ra n ge stat us ( L o w, N or mal, Hi g h)
C T C gra de ( wit h ass ociate d C T C na me)
Baseli ne fla g ( Yes/ N o )
W orst val ue o n -treat me nt fla g (Yes/ N o )
I n a d diti o n, a listi n g dis pla yi n g para meters wit h at least o ne val ue wit h gra de ≥ 3 will be pr o vi de d. 
F or eac h s u bject, o nl y  para meters w here at least o ne val ue has Gra de > = 3 will be dis pla y e d (all 
visits f or t he c orres p o n di n g para meter will be dis pla y e d).
C o a g ul ati o n p ar a meters
All c oa g ulati o n para meters will be liste d f or eac h meas ure me nt (pre -treat me nt, o n- treat me nt a n d 
p ost -treat me nt).
Uri n al ysis
A listi n g of uri nal ys is a n d micr osc o pic a nal ysis will be pr o vi de d.
1 5. 5
Vit al Si g ns
P o p ul ati o n: S A F a n alysis set
B o x pl ots will be pr o d uce d f or s yst olic bl o o d press ure , diast olic bl o o d press ure, heart rate, 
te m perat ure a n d wei g ht. T hese will be prese nte d b y  visit. O nl y s c he d ule d visits will be ta ke n i nt o 
acc o u nt.
Vital si g ns data fr o m “ Vital Si g ns” e C R F pa ges will be liste d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 /6 0
1 5. 6
Ot her S afet y or T oler a bilit y E v al u ati o ns
1 5. 6. 1
M acr osc o pic si g ns of blee di n g
P o p ul ati o n: S A F a n alysis set
T he macr osc o pic si g ns of blee di n g will be liste d at baseli ne a n d after a d mi nistrati o n of M 3 8 1 4 
usi n g data fr o m “ Ma cr osc o pic Si g ns of Blee di n g” e C R F pa ge.
1 5. 6. 2
E C O G Perf or m a nce St at us
P o p ul ati o n: S A F a n alysis set
T he listi n g will i ncl u de all t he data fr o m t he “E C O G Perf or ma nce Stat us ” e C R F secti o n.
A d diti o nall y , o ne s pa g hetti pl ot per f or m ulati o n/d ose le vel will be pr o d uce d, usi n g differe nt 
c ol ors/li ne t ypes per patie nt.  
1 5. 6. 3
E C G a n d Q T/ Q Tc e v al u ati o ns
P o p ul ati o n: S A F a n alysis set
Electr ocar di o gra m val ues base d o n “Tri plicate 1 2 -Lea d E C G” e C R F secti o n will be use d f or
s u m mar y statistics a n d s hift ta bles.
T he n u m ber of s u bjects wit h n or mal E C Gs at baseli ne a n d a b n or mal E C G s u n der treat me nt will 
be calc ulate d.
If tri plicate meas ure me nts are perf or me d at a ny ti me p oi nt, t he f oll o wi n g will a p pl y :

T he mea n of t he tri plicate meas ure me nt will be use d as s u m mar y  of t he q ua ntitati ve 
para meters

T he w orst O verall c o ncl usi o n will be retai ne d
A n y  u nsc he d ule d assess me nts t hat c o ul d be clearl y i de ntifie d as part of a tri plicate meas ure me nt 
s h o ul d be ta ke n i nt o acc o u nt. 
E C G para meters o n- treat me nt will be prese nte d b y  the f oll o wi n g fre q ue nc y ta ble ( by d ose le vel 
a n d o verall):

S hift fr o m n or mal baseli ne res ult t o a n y a b n or mal p ost -baseli ne res ult

W orst mea ns a bs ol ute Q Tc F i nter val p ost-baseli ne
o
> 4 5 0 ms a n d ≤ 4 8 0 ms
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 /6 0
o
> 4 8 0 ms a n d ≤5 0 0 ms
o
> 5 0 0 ms

W orst mea ns
Q Tc F i ncrease fr o m baseli ne
o
> 3 0 ms a n d ≤ 6 0 ms
o
> 6 0 ms
S u m mar y  ta bles will be pr o vi de d f or eac h visit a n d ti me p oi nt b y  dose le vel a n d o verall f or t he 
f oll o wi n g E C G para meters

Heart Rate

R- R d urati o n

P Q/ P R d urati o n

Q T d urati o n

Q R d urati o n

Q Tc F
E C G res ults (i nter pretati o n) will be s u m marize d usi n g a fre q ue nc y ta ble f or eac h visit a n d ti me 
p oi nt b y  d ose le vel a n d o verall.
Visits a n d ti me p oi nts t o be dis pla y e d i n s u m mar y ta bles are:
-
Baseli ne (c orres p o n di n g t o last meas ure me nt pri or t o t he first d ose of a n y trial treat me nt)
-
Fracti o n d a y 1 post -d ose (c orres p o n di n g t o E C G perf or me d at 2 h o urs p ost d ose f or 
s u bjects e nr olle d u n der pr ot oc ol V 1. 0 (c ollecte d i n “ec g 2” e C R F pa ge) a n d at 2 t o 3 
h o urs p ost d ose f or s u bjects e nr olle d u n der pr ot oc ol V 1. 0 or hi g her (c ollecte d i n “ec g 3” 
e C R F pa ge))
-
F racti o n da y 1 0
T w o listi n gs will dis pla y all t he res ults as prese nte d i n “ E C G” e C R F pa ge, o ne o n Q ualitati ve 
Res ults a n d a n ot her o ne o n Q ua ntitati ve Res ults. All visits a n d ti me p oi nts will be i ncl u de d i n 
listi n gs. 
1 5. 6. 4
Pre g n a nc y Test
Pre g na nc y  testi n g (ser u m β- H C G) will be perf or me d at scree ni n g a n d 3 0 da y s p ost -treat me nt. A 
listi n g will dis pla y all t he res ults as prese nte d i n “ Pre g na nc y Test” e C R F pa ge. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 /6 0
1 6
A n al yses of Ot her E n d p oi nts
1 6. 1
P h ar m ac o k i netics
P o p ul ati o n: P K a n alysis set
N o n -c o m part me ntal c o m p utati o n of P K para meters will be perf or me d usi n g t he c o m p uter pr o gra m 
P h oe ni x ®
Wi n N o nli n
®
versi o n 6. 4, or hi g her ( P harsi g ht C or p orati o n, a Certara C o m pa n y , 
Pri ncet o n, Ne w Jerse y). T he statistical s oft ware S A S ® ( Statistical A nal y sis S y ste m, S A S -I nstit ute, 
Car y  Nort h Car oli na), Wi n d o ws versi o n 9. 2 or hi g her will be use d t o pr o d uce ta bles, listi n gs a n d 
fi g ures. Fi g ures will be pre pare d wit h S A S Versi o n 9. 2, or hi g her.
P har mac o ki netic para meters will be calc ulate d usi n g sta n dar d n o n- c o m part me ntal met h o ds a n d 
t he act ual a d mi nistere d d ose. 
F or eac h s u bject wit h P K data, t he f oll o wi n g P K para meters will be calc ulate d f or M 3 8 1 4
a n d 
as eit her si n gle or m ulti ple d ose , as f oll o ws a n d as a p pr o priate. 

F D 1 – si n gle d ose

 – si n gle d ose if it occ urs o n a M o n da y 

A ll ot her fracti o n da ys - m ulti ple d ose .
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n 
C ma x / D ose
T he D ose -n or malize d ma xi m u m o bser ve d c o nce ntrati o n. N or malize d usi n g t he 
act ual d ose, a n d t he f or m ula C ma x / D ose.
A U C 0- 4
Area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me zer o t o ti me 4 h o urs 
p ost d ose. A U C 0- 4 will be base d o n t he esti mate d c o nce ntrati o n at 4 h o urs a n d n ot 
t he c o nce ntrati o n at t he act ual o bser vati o n ti me. F or  
 i n case n o re gressi o n is 
a vaila ble a n d a sa m ple has bee n c ollecte d at 4 h o urs wit hi n t he pr ot o c ol-defi ne d 
c ollecti o n wi n d o w ( 3. 5 t o 4. 5 h o urs), act ual ti me ma y be use d.
A U C 0- 4/ D ose T he D ose -n or malize d A U C fr o m ti me zer o t o 4 h o urs p ost d ose. N or malize d usi n g 
t he act ual d ose, usi n g t he f or m ula A U C 0- 4 / D ose. 
A U C 0- 6
Area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me zer o t o ti me 6 h o urs 
p ost d ose. A U C 0- 6 will be base d o n t he esti mate d c o nce ntrati o n at 6 h o urs a n d n ot 
t he c o nce ntrati o n at t he act ual o bser vati o n ti me. I n case n o re gressi o n is a vaila ble 
a n d a sa m ple has bee n c ollecte d at 6 h o urs wit h i n t he pr ot oc ol -defi ne d c ollecti o n 
wi n d o w ( 5. 5 t o 6. 5 h o urs), act ual ti me ma y be use d.
A U C 0- 6/ D ose T he D ose -n or malize d A U C fr o m ti me zer o t o 6 h o urs p ost d ose. N or malize d usi n g 
t he act ual d ose, usi n g t he f or m ula A U C 0- 6/ D ose. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 /6 0
A U C 0- 1 2
Area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me zer o t o ti me 1 2 h o urs 
p ost d ose. A U C 0- 1 2 will be base d o n t he esti mate d c o nce ntrati o n at 1 2 h o urs base d 
o n t he eli mi nati o n rate c o nsta nt.
A U C 0 -1 2/ D ose T he D ose -n or malize d A U C fr o m ti me zer o t o 1 2 h o urs p ost d ose. N o r malize d usi n g 
t he act ual d ose, usi n g t he f or m ula A U C 0- 1 2/ D ose. 
tma x
Ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n C ma x
tlast
T he last sa m pli n g ti me at w hic h t he c o nce ntrati o n is at or a b o ve t he l o wer li mit of 
q ua ntificati o n ( L L O Q).
R acc( C ma x)
Acc u m ula ti o n rati o f or Cma x , calc ulate d as Cma x
C ma x, F D 1 (all d ose gr o u ps)
F rel( C ma x)
Relati ve bi oa vaila bilit y f or C ma x
of ta blet c o m pare d t o ca ps ule f or m ulati o n 
C ma x, F D 1 / Cma x,
(ta blet testi n g gr o u p o nl y)
R acc( A U C 0 -4)
Acc u m ulati o n rati o f or A U C 0- 4 calc ulate d as A U C 0- 4
A U C 0- 4, F D 1 (all d ose 
gr o u ps)
F rel(A U C 0 - 4)
Relati ve bi oa vaila bilit y  for A U C 0- 4 of ta blet c o m pare d t o ca ps ule f or m ulati o n 
A U C 0- 4 , F D 1/A U C 0- 4
(ta blet testi n g gr o u p o nl y)
R acc( A U C 0 - 6)
Acc u m ulati o n rati o f or A U C 0- 6 calc ulate d as A U C 0- 6
A U C 0- 6 , F D 1 (all d ose 
gr o u ps)
R acc( A U C 0 -1 2 )
Acc u m ulati o n rati o f or A U C 0- 1 2 calc ulate d as A U C 0- 1 2
A U C 0- 1 2 , F D 1 (all d ose 
gr o u ps)
R acc( A U C 0 -2 4 )
Acc u m ulati o n rati o f or A U C 0- 2 4 calc ulate d as A U C 0- 2 4
A U C 0- 2 4 , F D 1 (all d ose 
gr o u ps)
F rel(A U C 0 - 2 4)
Relati ve bi oa vaila bilit y  for A U C 0- 2 4 of ta blet c o m pare d t o ca ps ule f or m ulati o n 
A U C 0- 2 4 , F D 1/ A U C 0- 2 4
(ta blet testi n g gr o u p o nl y)
A U C 0- 2 4
Area u n der t he c o nce ntrati o n-ti me c ur ve ( A U C) fr o m ti me zer o t o ti me 2 4 h o urs. 
A U C 0- 2 4 h will be calc ulate d after t he first d ose o n Fracti o n Da y  1 a n d after d osi n g 
o n Fracti o n Da y  6 (i n ta blet testi n g gr o u p o nl y ) a n d Fracti o n Da y 1 0. A U C0- 2 4 will 
be base d o n t he esti mate d c o nce ntrati o n at 2 4 h o urs, a n d n ot t he c o nce ntrati o n at 
t he act ual o bser vati o n ti me. F or F D 1 a n d 
 i n case n o re gressi o n is a vaila ble 
a n d a sa m ple has bee n c ollecte d at 2 4 h o urs wit hi n t he pr ot oc ol -defi ne d c ollecti o n 
wi n d o w ( 2 3. 5 t o 2 4. 5 h o urs), act ual ti me ma y  be use d. F or  
 w here a vaila ble, 
t he pre-d ose c o nce ntrati o n will be d u plicate d a n d use d as t he 2 4 h o ur c o nce ntrati o n 
t o all o w A U C0- 2 4 t o be calc ulate d (ass u mi n g stea d y state after m ulti ple d osi n g).
A U C 0- 2 4/ D ose T he D ose -n or malize d A U C fr o m ti me zer o t o 2 4 h o urs. N or malize d usi n g t he 
act ual d ose, usi n g t he f or m ula A U C 0- 2 4 / D ose. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C
C
C
C CI




M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 /6 0
ti me p oi nts a n d t he n u meric c o nce ntrati o n data. All c o nce ntrati o n-ti me pl ots f or P K data will be 
prese nte d b ot h o n a li near a n d o n a se mi -l o garit h mic scale. Mea n pl ots will i ncl u de S D err or bars 
w he n pl otte d o n a li near scale.
T he tr o u g h c o nce ntrati o ns ( Ctr o u g h) f or F D 2,  
 F D 7, a n d 
 will be liste d a n d s u m marize d 
b y  gr o u p (e. g. d ose le vel, fracti o n d a y , a nal yt e), usi n g sta n dar d descri pti ve statistics. I ndi vi d ual 
C tr o u g h val ues will be pl otte d a gai nst act ual ti me p oi nts o n a li near scale, f or all s u bjects b y  dose 
le vel. Arit h metic mea n Ctr o u g h  ± S D will als o be pl otte d b y  d ose le vel, o n a li near scale.
T he calc ulati o n of t he A U C will be perf or me d usi n g t he mi xe d l o g -li near tra pez oi dal met h o d. T he 
act ual ti me of bl o o d sa m pli n g will be use d f or P K para meter calc ulati o n. I n cases w here t he act ual 
sa m pli n g ti me is missi n g, calc ulati o ns will be perf or me d usi n g t he sc he d ule d ti me. 
Partial areas A U C 0 - 4 A U C 0- 6, A U C 0- 1 2, a n d A U C 0- 2 4 s h o ul d be calc ulate d usi n g t he sc he d ule d 
d osi n g i nter val. T he act ual i nter val calc ulate d fr o m C R F ti me data s h o ul d n ot be use d. 
Pre -d ose sa m ples will be c o nsi dere d as if t he y ha d bee n ta ke n si m ulta ne o usl y wit h t he 
a d mi nistrati o n, a n d will be assi g ne d a ti me of 0 h o urs. C o nce ntrati o ns bel o w t he l o wer li mit of 
q ua ntificati o n ( L L O Q), will be ta ke n as zer o f or s u m mar y statistics of P K c o nce ntrati o n data, N C A 
an d f or gra p hical prese ntati o ns .
T he re gressi o n a nal ys is s h o ul d c o ntai n data fr o m at least 3 differe nt ti me p oi nts i n t he ter mi nal 
p hase c o nsiste nt wit h t he assess me nt of a strai g ht li ne o n t he l o g-tra nsf or me d scale. P h oe ni x 
Wi n N o nli n “ best fit” met h o d ol o g y will be use d as sta n dar d. H o we ver, i n s o me cases, f urt her 
a dj ust me nt ma y  be ma de b y  the p har mac o ki neticist, if warra nte d, after a gree me nt wit h t he 
S p o ns or. T he last q ua ntifia ble c o nce ntrati o n s h o ul d al wa ys be i ncl u de d i n t he re gressi n a nal ys is, 
w hile t he c o nce ntrati o n at tma x a n d a n y co nce ntrati o ns bel o w L L O Q w hic h occ ur after t he last 
q ua ntifia ble data p oi nt s h o ul d n ot be use d . 
A U C e xtra s h o ul d n ot be greater t ha n 2 0 % , the c oefficie nt of c orrelati o n ( R²) s h o ul d be ≥0. 8 0 0 0 a n d 
t he o bser vati o n peri o d o ver w hic h t he re gressi o n li ne is esti mate d s h o ul d be at least t w of ol d t he 
res ulti n g t1/ 2 itself. If t hese criteria are n ot met, t he n t he rate c o nsta nts a n d all deri ve d para meters 
(e. g. C L/f, a n d Vz /f etc.) will be i ncl u de d i n t he para meter o ut p uts a n d descri pti ve statistics b ut will 
be fla g ge d a n d disc usse d a p pr o priatel y. A n y fla gs will be i ncl u de d i n t he st u d y specific 
S D T M / A Da M. 
Scatter pl ots a n d b o x pl ots of i n di vi d ual d ose -n or malize d C ma x , Ca v 0 - 2 4 , A U C 0- 4, A U C0- 6, A U C 0- 1 2, 
A U C 0- 2 4, a n d A U C0- ∞val ues vers us d ose will be prese nte d gra p hicall y.
All descri pti ve s u m maries of P K data will be perf or me d usi n g t he P K A nal ysis Set. I ndi vi d ual P K 
data will be liste d usi n g t he Safet y A nal ys is Set. T he mea n c o nce ntrati o n-ti me pr ofiles a n d P K 
para meter pl ots will be pl otte d usi n g t he P K A nal y sis Set a n d t he i n di vi d ual s u bject c o nce ntrati o n -
ti me pr ofiles will use t he Safet y  Anal ys is Set. E x pl orat or y  dose pr o p orti o nalit y  anal ys is will be 
perf or me d b y  vis ual i ns pecti o n of t he scatter pl ots a n d b o x pl ots of C ma x / d ose a n d A U C 0- 4/ d ose 
a gai nst d ose.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 /6 0
T he P h oe ni x Wi n N o nli n N C A C ore O ut p ut will be pr o vi de d i n a se parate listi n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 /6 0
 
1 7
Refere nces
1.
Ba b b J, R o gat k o A, Zac ks S. Ca ncer p hase I cli nical trials: Efficie nt d ose escalati o n wit h 
o ver d ose c o ntr ol. Stat Me d 1 9 9 8; 1 7( 1 0): 1 1 0 3 - 2 0.
2.
Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he B a y esia n a p pr oac h t o P hase 
I ca ncer trials. Stat Me d 2 0 0 8; 2 7( 1 3): 2 4 2 0- 3 9.
3.
S weeti n g M, Ma n der A, Sa bi n T. Ba ye sia n C o nti n ual Reassess me nt Met h o d Desi g ns f or P hase 
I D ose -Fi n di n g Trials. J Stat S oft w 2 0 1 3; 5 4: 1 -2 6. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI




M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 /6 0
2. Eli gi bilit y  a n d E ntr y Criteria
P hase Ia: Patie nt d oes n ot ha ve 
a d va nce d s oli d t u m ors or metastases 
i ncl u di n g ly m p h o ma l ocalize d i n t he 
hea d a n d nec k re gi o n or t h ora x wit h a n 
i n dicati o n f or fracti o nate d palliati ve 
R T ( Ar m A);
or is n ot treat me nt -naï ve S C C H N 
eli gi ble f or fracti o nate d c urati vel y 
i nte n de d R T wit h c o nc urre nt cis plati n 
( Ar m B)
P hase I b: patie nt is n ot  treat me nt-
naï ve Sta ge III A/ B N S C L C n ot 
eli gi ble f or s ur gical resecti o n or 
c o nc urre nt c he m ora diati o n ( Ar m A 
e x pa nsi o n c o h ort) 
or treat me nt -naï ve S C C H N eli gi ble f or 
fracti o nate d c urati vel y i nte n de d R T 
wit h c o nc urre nt cis plati n ( Ar m B 
e x pa nsi o n c o h ort)
c P o P: pati e nt d oes n't ha ve t u m or wit h 
at least 2 (s u b)c uta ne o us 
t u m or/ metastases at least 2 c m a part 
w hic h are R T naï ve wit h a n i n dicati o n 
f or hi g h d ose palliati ve R T
P D E V 8
Y
2. Eli gi bilit y  a n d E ntr y Criteria
E C O G P S > 1
P D E V 9
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 /6 0
2. Eli gi bilit y  a n d E ntr y Criteria
Patie nt is n ot a ble t o rea d,  u n dersta n d, 
a n d si g n a n d date t he I nf or me d 
C o nse nt F or m (I C F); or f ull y  
u n dersta n d t he re q uire me nts of t he trial 
a n d is n ot willi n g t o c o m pl y wit h all 
trial visits a n d assess me nts
P D E V 1 0
N
2. Eli gi bilit y  a n d E ntr y Criteria
Life e x pecta nc y  < 3 m o nt hs
P D E V 1 1
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bject d oes n ot ha ve a de q uate 
he mat ol o gical f u ncti o n, defi ne d as  
a bs ol ute ne utr o p hil c o u nt ≥ 1. 0 × 
1 0 9/ L ,  platelet c o u nt ≥ 1 0 0 × 1 0 9/ L , 
a n d he m o gl o bi n ≥ 1 0 g/ d L , ie 5. 7 
m m ol/ L  
P D E V 1 2
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bject d oes n ot ha ve a n a de q uate li ver 
f u ncti o n, defi ne d by t otal bilir u bi n 
> 1. 5 × U L N or as partate 
a mi n otra nsferase ( A S T)/ala ni ne 
a mi n otra nsferase ( A L T) > 2. 5 × U L N 
(e xce pt f or s u bjects wit h li ver 
i n v ol ve me nt, w h o ca n ha ve A S T/ A L T 
> 5 × U L N)
P D E V 1 3
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bject d oes n ot ha ve a n a de q uate 
re nal f u ncti o n, e vi de nce d b y ser u m 
creati ni ne > 1. 5 × u p per li mit of n or mal 
( U L N)
P D E V 1 4
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 /6 0
2. Eli gi bilit y  a n d E ntr y Criteria
A male s u bject di d n ot utilize a hi g hl y  
effecti ve c o ntrace pti o n (ie, met h o ds 
wit h a fail ure rate of less t ha n 1 % per 
ye ar) as detaile d i n A p pe n di x II 
res ulti n g i n a pre g na nc y or d o nate d 
s per m d uri n g
t he treat me nt peri o d, a n d f or at least 
9 0 da y s after t he last d ose of st u d y 
treat me nt
P D E V 1 5
N
2. Eli gi bilit y  a n d E ntr y Criteria
A fe male s u bjects di d n ot utilize hi g hl y  
effecti ve c o ntrace pti o n w hic h has 
res ulte d i n a pre g na nc y d uri n g t he 
treat me nt peri o d or f or at least 9 0 da ys 
aft t her last d oes of st u d y treat me nt.  
P D E V 1 6
N
2. Eli gi bilit y  a n d E ntr y Criteria
Use of ot her a ntica ncer t hera p y, 
C he m ot hera p y, i m m u n ot hera p y, 
h or m o nal t hera p y, bi ol o gic t hera p y 
wit hi n 2 8 da y s bef ore t he first d ose of 
M 3 8 1 4 
P D E V 1 7
N
2. Eli gi bilit y  a n d E ntr y Criteria
Resi d ual t o xicit y  d ue t o pre vi o us 
a ntica ncer t hera p y wit h n o ret ur n t o 
baseli ne or Gra de ≤ 1 (e xce pt al o pecia) 
acc or di n g t o C T C A E V 4. 0 3
P D E V 1 8
N
2. Eli gi bilit y  a n d E ntr y Criteria
E xte nsi ve pri or R T o n m ore t ha n 3 0 % 
of b o ne marr o w reser ves ( b y  
I n vesti gat or j u d g me nt), or pri or b o ne 
marr o w / ste m cell tra ns pla ntati o n 
wit hi n 5 y ears bef ore st u d y start
P D E V 1 9
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 /6 0
2. Eli gi bilit y  a n d E ntr y Criteria
Pri or R T t o t he sa me re gi o n t hat w o ul d 
be irra diate d i n t his st u d y wit hi n 1 2 
m o nt hs ( Ar m A) or a n y t i me ti me 
pre vi o usl y  ( Ar m B)
P D E V 2 0
N
2. Eli gi bilit y  a n d E ntr y Criteria
S ur gical i nter ve nti o n wit hi n 2 8 da y s 
pri or t o t he first d ose of M 3 8 1 4 
a d mi nistrati o n (e xce pt f or dia g n ostic 
nee dle  bi o ps y)
P D E V 2 1
N
2. Eli gi bilit y  a n d E ntr y Criteria
Si g nifica nt car diac c o n d ucti o n 
a b n or malities, i ncl u di n g a hist or y  of 
l o n g c orrecte d Q T i nter val ( Q Tc) 
s yn dr o me a n d / or pace ma ker, or 
i m paire d car di o vasc ular f u ncti o n s uc h 
as Ne w Y or k Heart Ass ociati o n 
classificati o n sc ore > 2
P D E V 2 2
N
2. Eli gi bilit y  a n d E ntr y Criteria
H y perte nsi o n u nc o ntr olle d b y  
me dicati o n
P D E V 2 3
N
2. Eli gi bilit y  a n d E ntr y Criteria
K n o w n C N S metastases u nless 
pre vi o usl y  treate d b y R T, sta ble b y 
c o m p ute d t o m o gra p h y ( C T) sca n f or at 
least 3 m o nt hs wit h o ut e vi de nce of 
cere bral e de ma a n d n o re q uire me nt f or 
c ortic oster oi ds or a ntic o n v ulsa nts
P D E V 2 4
N
2. Eli gi bilit y  a n d E ntr y Criteria
K n o w n h u ma n i m m u n o deficie nc y  
vir us ( HI V) p ositi vit y , k n o w n 
cli nicall y si g nifica nt hist or y of 
he patitis (e. g., He patitis B [ H B V] or 
He patitis C [ H C V] vir us), c urre nt 
alc o h ol a b use, or cirr h osis. Scree ni n g 
f or HI V t o be perf or me d acc or di n g t o 
P D E V 2 5
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 /6 0
l ocal practice a n d l ocal re g ulat or y 
g ui da nce. Testi n g f or HI V a n d 
H B V/ H C V s h o ul d be re peate d if t he 
s u bject teste d ne gati ve f or t he vir uses 
m ore t ha n 3 m o nt hs bef ore trial 
e nr oll me nt
2. Eli gi bilit y  a n d E ntr y Criteria
O n g oi n g acti ve i nfecti o n (re q uiri n g 
s yste mic treat me nt) or treat me nt wit h 
li ve or li ve atte n uate d vacci ne wit hi n 
3 0 da y s of d osi n g
P D E V 2 6
N
2. Eli gi bilit y  a n d E ntr y Criteria
Hist or y  of diffic ult y s wall o wi n g, 
mala bs or pti o n or ot her c hr o nic 
gastr oi ntesti nal disease or c o n diti o ns 
t hat ma y ha m per c o m plia nce a n d/ or 
a bs or pti o n of t he I M P, c urre nt use of 
perc uta ne o us e n d osc o pic gastr ost o m y 
( P E G) t u bes
P D E V 2 7
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bjects c urre ntl y recei vi n g H 2 -
bl oc ker or pr ot o n p u m p i n hi bit ors 
( P PIs) ( or u na ble t o st o p at least 5 da ys 
pri or t o t he first treat me nt).
P D E V 2 8
N
2. Eli gi bilit y  a n d E ntr y Criteria
If t he pla n ne d ra diati o n fiel d i ncl u des 
a n y part of t he es o p ha g us a n d t he 
s u bject has sy m pt o ms of o n g oi n g 
es o p ha gitis, t he s u bject is n ot eli gi ble, 
u nless a n es o p ha geal e n d osc o p y  r ules 
o ut t he prese nce of es o p ha gitis.
P D E V 2 9
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bjects w here m ore t ha n 1 0 % of t he 
t otal es o p ha g us v ol u me recei ves m ore 
t ha n 5 0 % of t he prescri be d R T d ose
P D E V 3 0
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 /6 0
2. Eli gi bilit y  a n d E ntr y Criteria
Hist or y  of a n y ot her si g nifica nt 
me dical disease s uc h as maj or gastric 
or s mall b o wel s ur ger y , rece nt drai na ge 
of si g nifica nt v ol u mes of ascites or 
ple ural eff usi o n or a ps yc hiatric 
c o n diti o n t hat mi g ht i n t he assess me nt 
of t he I n vesti gat or precl u de 
partici pati o n i n t he st u d y
P D E V 3 1
N
2. Eli gi bilit y  a n d E ntr y Criteria
K n o w n h y perse nsiti vit y  or aller gic 
reacti o n t o t he st u dy treat me nts or t o 1 
or m ore of t he e xci pie nts use d
P D E V 3 2
N
2. Eli gi bilit y  a n d E ntr y Criteria
Pre g na nt or breast -fee di n g
P D E V 3 3
N
2. Eli gi bilit y  a n d E ntr y Criteria
S u bjects c urre ntl y recei vi n g or u na ble 
t o st o p usi n g me dicati o ns or her bal 
s u p ple me nts k n o w n t o be p ote nt 
i n hi bit ors of C Y P 3 A or P-g p ( C Y P a n d 
/ P-g p m ust st o p at least 1 wee k bef ore 
treat me nt wit h M 3 8 1 4 ) or p ote nt 
i n d ucers of C Y P 3 A or P-g p ( m ust st o p 
at least 3 wee ks
bef ore treat me nt wit h M 3 8 1 4 ) or dr u gs 
mai nl y  meta b olize d b y C Y P 3 A wit h a 
narr o w t hera pe utic i n de x ( m ust st o p at 
least 1 da y pri or). 
P D E V 3 4
N
2. Eli gi bilit y  a n d E ntr y Criteria
Le gal i nca pacit y or li mite d le gal 
ca pacit y.
P D E V 3 5
N
3. C o nc o mita nt Me dicati o n Criteria
T he s u bject was treate d wit h a 
me dici ne f or bi d de n b y t he pr ot oc ol 
(secti o n 6. 5. 2) w hile o n treat me nt
P D E V 3 9
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 /6 0
3. C o nc o mita nt Me dicati o n Criteria
A n y  i n vesti gati o nal or a ntica ncer 
t hera py gi ve n c o nc o mita ntl y  w hile 
patie nt is o n st u d y treat me nt
P D E V 4 0
N
4. L a b orat or y Assess me nt Criteria
Misse d e ntire safet y  la b orat or y  at t he 
s pecifie d ti me p oi nt 
P D E V 4 1
N
4. L a b orat or y Assess me nt Criteria
Scree ni n g la bs are n ot wit hi n 2 1 da y s 
bef ore t he start of t he treat me nt 
P D E V 4 5
N
4. La b orat or y Assess me nt Criteria  
N o p ost -d ose P K sa m ple c ollecte d
P D E V 4 7
N
4. L a b orat or y Assess me nt Criteria
M ore t ha n 2 P K ti me p oi nts misse d
P D E V 4 9
N
4. L a b orat or y Assess me nt Criteria
P K sa m ples n ot i n li ne wit h sc he d ule 
of c ollecti o n defi ne d i n t he pr ot oc ol 
a n d o utsi de of wi n d o ws,  defi ne d f or 
mi n or P Ds
P D E V 5 1
N
4. L a b orat or y Assess me nt Criteria
Neit her pre d ose n or p ost d ose sa m ple 
f or at least o ne bi o mar ker assess me nt 
c ollecte d
P D E V 5 2
N
5. St u d y  Pr oce d ures Criteria
Scree ni n g t u m or assess me nt (e xce pt 
C T sca n, w hic h is all o we d u p t o 2 8 
da y s ) d o ne o utsi de of all o wa ble 2 1 
da y  wi n d o w.
P D E V 3 6
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 /6 0
5. St u d y  Pr oce d ures Criteria
Ke y  scree ni n g tests/assess me nts n ot 
d o ne: 
T u m or s peci me n n ot c ollecte d
Pre g na nc y  test n ot perf or me d
C o m plete vital si g ns a n d p h y sical 
e xa mi nati o n is missi n g
Cli nical e val uati o n of blee di n g is 
missi n g
E ntire he mat ol o gical pa nel is missi n g
E ntire c he mistr y  pa nel is missi n g
E ntire c oa g ulati o n pa nel is missi n g
Missi n g uri nal ys is
Missi n g E C G 
Es o p ha geal e n d osc o p y n ot perf or me d, 
t h o u gh n o c o nfir mati o n o n a bse nce of 
es o p ha gitis (starti n g fr o m Pr ot oc ol 
v 8. 0/ 8. 1)
P D E V 3 7
N
5. St u d y  Pr oce d ures Criteria
P h y sical e xa m, E C O G Perf or ma nce, 
vital si g ns, E C G n ot perf or me d at 
re q uire d ti me p oi nt   f or 2 or m ore 
c o nsec uti ve visits
P D E V 5 3
N
5. St u d y  Pr oce d ures Criteria
E C Gs missi n g o n 2 or m ore s u bse q ue nt 
visits 
P D E V 5 7
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 /6 0
5. St u d y  Pr oce d ures Criteria
c P o P patie nts: bi o ps y d o ne o utsi de of 
t he wi n d o w, s pecifie d by pr ot oc ol ( 2 - 4 
hrs p ost R T) a n d m ore t ha n +/ -3 0 mi n
P D E V 5 9
N
5. St u d y  Pr oce d ures Criteria
Treat me nt n ot disc o nti n ue d after 
wit h dra wal criteria defi ne d at pr ot oc ol 
secti o n 5. 5 are met: 
Patie nt wit h dra wal of c o nse nt at a n y 
ti me
A n y  reas o n w here t he i n vesti gat or 
c o nsi ders t hat wit h dra wal is i n t he best 
i nterest of t he patie nt
Pre g na nc y
T reat me nt dela y f or greater t ha n 3 
fracti o n da ys
Lac k of c o m plia nce wit h t he st u d y  
a n d/ or st u d y pr oce d ures (e. g. d osi n g 
i nstr ucti o ns, st u d y visits) 
P D E V 6 0
N
6. Seri o us A d verse E ve nt Criteria
S A E(s) were n ot re p orte d or n ot 
re p orte d wit hi n 2 4 h o urs of site's 
a ware ness ( disc o vere d b y C R As d uri n g 
S D V)
P D E V 6 1
N
6. Seri o us A d verse E ve nt Criteria
Pre g na nc y  was n ot re p ore d ( disc o vere d 
b y  C R As d uri n g S D V)
P D E V 6 2
N
8. Visit Sc he d ule Criteria
E O T Visit n ot d o ne
P D E V 6 3
N
8. Visit Sc he d ule Criteria
Treat me nt Visits n ot 
perf or me d/c o m plete d i n a bse nce of 
j ustif yi n g A E/ S A E
P D E V 6 4
N
8. Visit Sc he d ule Criteria
Visits perf or me d o utsi de of wi n d o w 
d uri n g D L T peri o d
P D E V 6 5
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 /6 0
8. Visit Sc he d ule Criteria
S u bject(s) l ost t o f oll o w u p wit hi n 
D L T peri o d
P D E V 6 7
N
8. Visit Sc he d ule Criteria
S u bject(s) l ost t o f oll o w u p o utsi de of 
D L T peri o d
P D E V 6 8
N
9. I P C o m plia nce
Treat me nt c o m plia nce: Patie nt n ot 
d ose d per pr ot oc ol.
D ose d after R T
I P was s ki p pe d, b ut R T c o nti n ue d i n 
a bse nce of A E j ustif yi n g I P wit h dra wal
I P was gi ve n, b ut R T s ki p pe d
Act ual d ose differe nt fr o m pla n ne d 
d ose o n at least o ne fracti o n da y
I P f or m ulati o n is differe nt fr o m 
assi g ne d
P D E V 6 9
N
9. I P C o m plia nce
Treat me nt c o m plia nce: patie nt 
o ver d ose d a n d n ot re p orte d
P D E V 7 0
N
9. I P C o m plia nce
I P was gi ve n o utsi de of pr ot oc ol 
s pecifie d wi n d o w bef ore R T:
T he wi n d o w e xcee de d all o we d f or 
mi n or P D wi n d o w, i.e. less t ha n 3 0 or 
m ore t hat 2. 5 hrs bef ore R T
P D E V 7 2
N
9. I P C o m plia nce
Treat me nt c o m plia nce: Patie nt di d n ot 
recei ve at least 8 0 % of pla n ne d d ose i n 
t he o verall treat me nt peri o d f or at least 
o ne treat me nt (i.e. R T a n d M 3 8 1 4.) 
Patie nts wit h t his pr ot oc ol de viati o n 
a n d wit h n o D L T e ve nt will be 
e xcl u de d fr o m D L T a nal ysis. 
S P E CI F Y o verall a m o u nt of d oses 
P D E V 7 3
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 /6 0
a d mi nistere d i n t he 1 0 fracti o n da y s 
( Ar m A) or 3 3- 3 5 F Ds ( Ar m B)
9. I P C o m plia nce
E ve nt of te m perat ure e xc ursi o n of I P. 
P D E V 7 4
N
9. I P C o m plia nce
E ve nt of te m perat ure e xc ursi o n a n d 
st u d y dr u g was a d mi nistere d t o patie nt 
( pri orit y if s u p ply ca n c o nfir m t hat 
dr u g s h o ul d n ot ha ve bee n use d)
P D E V 7 5
N
9. I P C o m plia nce
Patie nt recei ves e x pire d or da ma ge d 
st u d y dr u g
P D E V 7 6
N
1 0. Efficac y  Criteria
N o baseli ne R E CI S T 1. 1 assess me nt 
o n or bef ore date of first d ose or 
o utsi de t he wi n d o w all o we d acc or di n g 
t o t he pr ot oc ol
P D E V 7 7
N
1 0. Efficac y  Criteria
1 or m ore c o nsec uti ve t u m or 
assess me nts n ot d o ne
P D E V 7 8
N
1 0. Efficac y  Criteria
T u m or assess me nts n ot perf or me d as 
per t he sc he d ule/ ti me p oi nt i n t he 
pr ot oc ol (if e xcee ds wi n d o w pr o vi de d 
f or mi n or P D)
P D E V 8 1
N
1 1. A d mi nistrati ve Criteria
Staff perf or mi n g st u d y relate d 
pr oce d ures pri or t o ha vi n g bee n 
dele gate d t he res p o nsi bilit y  o n t he Site 
Pers o n nel Si g nat ure Dele gati o n L o g
P D E V 8 2
N
1 2. S o urce D oc u me nt Criteria
Me dical rec or ds n ot pr o vi de d t o t he 
m o nit or f or S D V of S A Es
P D E V 8 3
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M S C 2 4 9 0 4 8 4 A
( M 3 8 1 4)
      P h ase I tri al of M S C 2 4 9 0 4 8 4 A i n C o m bi n ati o n wit h R a di ot her a p y
E M R 1 0 0 0 3 6 - 0 0 2
       Versi o n 3. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 /6 0
1 2. S o urce D oc u me nt Criteria
S u bject d oc u me nts se nt t o st u d y  tea m/ 
o utsi de of t he i nstit uti o n wit h patie nt 
i de ntifiers details
P D E V 8 4
N
1 2. S o urce D oc u me nt Criteria
I nf or me d c o nse nt disc ussi o n a n d 
pr o visi o n of c o p y of I C F t o patie nt n ot 
d oc u me nte d i n t he Me dical rec or ds
P D E V 8 5
N
1 2. S o urce D oc u me nt Criteria
F ull me dical rec or ds n ot pr o vi de d t o 
t he m o nit or f or S D V
P D E V 8 6
N
1 3. Re g ulat or y or Et hics A p pr o vals 
Criteria
Treat me nt of s u bject bef ore recei pt of 
I RB a p pr o val
P D E V 9 0
N
1 3. Re g ulat or y or Et hics A p pr o vals 
Criteria
Ne w pr ot oc ol n ot i m ple me nte d or 
u p date d I C F n ot use d after I R B/I E C 
a n d re g ulat or y a p pr o val
P D E V 9 1
N
1 3. Re g ulat or y or Et hics A p pr o vals 
Criteria
Ot her st u d y  s pecific d oc u me nts (a d mi n 
c ha n ge, safet y car ds) a n d ot her patie nt 
s pecific d oc u me nts use d pri or t o 
I RB/I E C a p pr o val
P D E V 9 2
N
1 3. Re g ulat or y or Et hics A p pr o vals 
Criteria
As per t he site I R B's 
g ui deli nes/ p olicies, site di d n ot re p ort 
de viati o ns t o I R B i n a ti mel y  ma n ner
P D E V 9 5
N
1 3. Re g ulat or y or Et hics A p pr o vals 
Criteria
As per t he site I R B's 
g ui deli nes/ p olicies, site di d n ot re p ort 
S A Es t o I R B i n a ti mel y  ma n ner
P D E V 9 6
N
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI


E L E C T R O NI C SI G N A T U R E S
D oc u me nt: ct p-e mr 1 0 0 0 3 6- 0 0 2-i a p- p h 1 a- v 3
Si g ne d B y
E ve nt N a me
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y
H H: m m ‘ G M T’ Z)
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
0 2- Se p- 2 0 2 0 0 9: 3 1
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
0 3- Se p- 2 0 2 0 1 4: 4 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
P P D
P P D