A Phase 2 Study of Oral LOXO-305 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)
Phase: PHASE2
Conditions: Leukemia, Lymphoid, Lymphoma, Non-Hodgkin, Lymphoma, Mantle-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, B-Cell, Lymphoma, B-Cell, Marginal Zone, Leukemia, Lymphocytic, Chronic, B-Cell
Sponsor: Eli Lilly and Company

 
 
 
Protocol J2N-MC-JZNJ (b) 
 
 
A Phase 2 Study of Oral LOXO-305 in Patients with Previously Treated Chronic Lymphocytic 
Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL) 
 
 
NCT04849416 
 
Approval Date: 16-Jul-2021 
 
 
 
 
 
 

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 1
L Y 3 5 2 7 7 2 7
Pr ot o c ol J 2 N -M C -J Z N J ( b)
A P h a s e 2 St u d y  of Or al L O X O-3 0 5 i n P ati e nt s wit h Pr e vi o u sl y  
Tr e at e d C hr o ni c L y m p h o c y ti c L e u k e mi a/ S m all L ym p h o c y ti c 
L y m p h o m a ( C L L/ S L L) or N o n -H o d g ki n L y m p h o m a ( N H L)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al 
i n v e sti g at or s.  It i s t h e pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e 
c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n t h e cli ni c al i n v e sti g ati o n of L O X O -3 0 5 
( L Y 3 5 2 7 7 2 7), u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y a gr e e m e nt wit h Eli Lill y a n d 
C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:   T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or 
c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e.  Eli Lill y a n d C o m p a n y 
r eq u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e.  I n t h e U nit e d 
St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 a n d m a y n ot 
b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or 
it s s u b si di ari e s.
L O X O -3 0 5 ( L Y 3 5 2 7 7 2 7)
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n: 2 0 A u g u st 2 0 2 0
A m e n d m e nt ( a) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n: 0 1 M ar c h 2 0 2 1
A m e n d m e nt ( b) El e ctr o ni c all y Si g n e d a n d A p pr o v e d b y Lill y o n a p pr o v al d at e pr o vi d e d 
b el o w:
A p pr o v al D at e: 1 6- J ul- 2 0 2 1 G M T

J2N-MC-JZNJ (b) Clinical Protocol
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SYNOPSIS
TITLE: 
A Phase 2 Study of Oral LOXO-305 in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)
PROTOCOL NUMBER: 
J2N-MC-JZNJ
STUDY SITES: 
Approximately 20 to 25 institutions in China are planned for participation in this study.
PHASE:
Phase 2
OBJECTIVES AND ENDPOINTS:
Objectives
Endpoints
Primary

To assess the anti-tumor activity of LOXO-305 
based on ORR according to Lugano Treatment 
Response Criteria for MCL and other NHL 
(Appendix A), International Workshop 
Guidelines for CLL/SLL (IWCLL 2018,
Appendix B) and WM (IWWM, Appendix C), 
or other criteria as appropriate to tumor type, as 
assessed by an IRC

ORR by IRC
Secondary

To assess, for each cohort, the anti-tumor 
activity of LOXO-305

ORR (by investigator)

BOR (by investigator and IRC)

DOR (by investigator and IRC)

PFS (by investigator and IRC)

OS

To determine the safety profile and tolerability 
of LOXO-305.

AEs, SAEs and TEAEs, changes in hematology 
and blood chemistry values, assessments of 
physical examinations, vital signs and ECGs. 

To characterize the PK properties of LOXO-
305.

Plasma concentration of LOXO-305 and PK 
parameters including, but not limited to, 
AUC0-24, Cmax, Tmax, T1/2

To determine the association of clinical 
response categories

Symptomatic response: improvement in cancer-
related symptoms among patients with MCL 
associated with BOR

Functional response: improvement in physical 
function among patients with MCL associated 
with BOR

To collect PRO data to explore disease-related 
symptoms and HRQoL

Changes from baseline in disease-related 
symptoms and HRQoL measured by EORTC 
QLQ-C30

To determine the relationship between PK and 
drug effects, including efficacy and safety

Differences in efficacy and safety based on 
LOXO-305 PK parameters
Abbreviation: AE = adverse event; AUC0-24 = area under the concentration versus time curve from time 0 to 24 hours; 
BOR = best overall response; Cmax = maximum drug concentration; CLL = chronic lymphocytic leukemia; DOR = 
duration of response; ECGs = electrocardiograms; EORTC QLQ-C30 = European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; HRQoL = health-related quality of life; IRC = 
Independent Review Committee; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; ORR = overall 

J2N-MC-JZNJ (b) Clinical Protocol
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response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; PRO = patient reported 
outcomes; SAE = serious adverse event; SLL = small lymphocytic lymphoma; T1/2 = terminal elimination half-life; 
TEAE = treatment emergent adverse event; Tmax = time to maximum plasma concentration; WM = Waldenström 
macroglobulinemia.
STUDY DESIGN:
This is an open-label, multi-center phase 2 study to evaluate efficacy and safety of oral LOXO-305 as monotherapy in 
patients with MCL, CLL/SLL and other types of B-cell NHL who have failed or are intolerant (as per the definitions in 
Appendix D) to standard of care.
The recommended phase 2 dose is 200 mg once daily (QD).  Patients will be enrolled to 1 of 3 cohorts depending on 
tumor histology and prior treatment history.  Cycle length will be 28 days.
The Study Schema is provided in Synopsis Figure 1: Study Schema.
At least 30 patients for Cohort 1, up to 30 patients for Cohort 2, and up to 50 patients for Cohort 3 are planned, thus
approximately ~ 120 patients will be enrolled across all cohorts. (refer to Synopsis Figure 1: Study Schema):

Cohort 1: Non-blastoid MCL patients with no central nervous system (CNS) metastases and treated with prior
chemoimmunotherapy (refer to Synopsis Table 1) and a BTK-inhibitor (refer to Appendix E) containing regimen 

Cohort 2: CLL/SLL patients treated with a prior BTK inhibitor containing regimen

Cohort 3:
o
MCL or CLL/SLL patients not meeting the definitions of Cohort 1 or Cohort 2 and having failed or intolerant to 
standard of care, or unsuitable for standard of care in the opinion of investigator; 
o
Other B cell NHL (include but not limited to DLBCL, MZL and WM) patients having failed or intolerant to standard 
of care, or unsuitable for standard of care in the opinion of investigator.
1.“Others” Cohort for:
a.
MCL or CLL/SLL patients not meeting the definitions of Cohort 1 or Cohort 2 and having failed or intolerant 
to standard of care, or unsuitable for standard of care in the opinion of investigator; 
b.
Other B cell NHL (include but not limited to DLBCL, MZL and WM) patients having failed or intolerant to 
standard of care, or unsuitable for standard of care in the opinion of investigator. 
Abbreviations:  BTK = Bruton’s tyrosine kinase; BTKi = BTK inhibitor; CLL = chronic lymphocytic leukemia; 
DLBCL = diffuse large B cell lymphoma; MCL = mantle cell lymphoma; MZL = marginal zone lymphoma; NHL = 
non-Hodgkin lymphoma; PD = progressive disease; QD = once daily; SLL = small lymphocytic lymphoma; WM = 
Waldenström macroglobulinemia.
Synopsis Figure 1:  Study Schema

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Synopsis Table 1: Chemoimmunotherapy for MCL
Cohort
Therapy (including but not limited to)
Cohort 1: Non-blastoid MCL patients with 
no CNS metastases and treated with prior 
chemoimmunotherapy and BTK-inhibitor 
containing regimen
1.
high dose cytarabine based therapy: (e.g., R-CHOP/R-DHAP, R-
hyperCVAD)
2.
rituximab based therapy (e.g., R-CHOP, BR, VR-CAP)
Inclusion Criteria:
1. Patients with histologically confirmed B-cell malignancy including:

Cohort 1 MCL: Confirmed diagnosis of non-blastoid MCL with no CNS metastases and with documentation 
of overexpression of cyclin D1 and/or t(11;14) and treated with prior chemoimmunotherapy and a BTK 
inhibitor containing regimen;

Cohort 2 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 criteria treated with a prior BTK 
inhibitor containing regimen;

Cohort 3 Others: Confirmed diagnosis of CLL/SLL by IWCLL 2018 criteria, WM with documentation of 
MYD88 mutation, MCL and other types of B-cell NHL (including but not limited to DLBCL and MZL) by 
WHO 2016 criteria, not otherwise specified in Cohort 1 and 2, and having failed or intolerant to standard of 
care, or unsuitable for standard of care in the opinion of investigator.
For patients in each Cohort:

All patients must have disease requiring treatment;

Documented evidence of patients having failed or intolerant on the most recent line of therapy or relapse prior 
to study enrollment is required; 

Patients in Cohort 1 and 2, relapsed/refractory or intolerant (as per the definitions in Appendix D) to a prior 
BTK inhibitor (investigational or approved, and either alone or in combination with other agents) treatment is 
required;

Patients with MCL in Cohort 1 who will be evaluated by Lugano criteria must have at least 1 site of 
radiographically assessable disease (i.e., lymph node longest diameter (LDi) >1.5 cm, extra nodal site >1.0 cm 
in LDi, or unequivocal hepatomegaly or splenomegaly due to disease). Patients with non-measurable disease 
are eligible and will be assigned to Cohort 3;

For CLL/SLL patients, at least 1 indication for treatment consistent with IWCLL 2018 criteria (refer to 
Appendix F) is required. 
2. Eastern Cooperative Oncology Group (ECOG)0-2.
3. At least 18 years of age.
4. Confirmation of availability of tumor sample along with pathology report for central pathology review as described 
in Section 7.4 of the Protocol for patients enrolled in Cohort 1.
5. Adequate hematologic status, defined as the following on or within 7 days of C1D1 before treatment: 
a.
Absolute neutrophil count (ANC) ≥0.75×109/L without granulocyte-colony stimulating factor (GCSF)
supporting within 7 days of Screening assessment; the patient may enroll below this threshold if there is 
documented bone marrow involvement considered to impair hematopoiesis.
b.
Platelet count ≥50 × 109/L not requiring transfusion or growth factors supporting within 7 days of Screening 
assessment; the patient may enroll below this threshold if there is documented bone marrow involvement 
considered to impair hematopoiesis.
c.
Hb ≥8 g/dL not requiring transfusion or growth factors supporting within 7 days of Screening assessment; the 
patient may enroll below this threshold if there is documented bone marrow involvement considered to impair 
hematopoiesis.
d.
Patients must be responsive to blood or platelets transfusion support if given for bone marrow involvement 
induced cytopenias.  Patients refractory to transfusion support are not eligible.  See also exclusion criteria item 
18.
6. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) and prothrombin time (PT) or 
(international normalized ration [INR]) not greater than 1.5 × upper limit of normal (ULN).
7. Adequate hepatic function, defined as:
a.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN with 
documented liver metastases;
b.
Total bilirubin ≤1.5 × ULN or ≤3 × ULN with documented liver metastases and/or Gilbert’s Disease. If total 

J2N-MC-JZNJ (b) Clinical Protocol
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bilirubin is >1.5 × ULN then direct/indirect or conjugated/unconjugated bilirubin tests should be performed for
patients with hemolysis and/or Gilbert’s syndrome, they may be enrolled if unconjugated/indirect bilirubin is 
<5 × ULN with sponsor approval.
8. Adequate renal function defined as creatinine clearance of ≥30 mL/ minute using Cockcroft/Gault Formula: 
(140 – age) × body weight (kg) × 0.85 (if female)
serum creatinine (mg/dL) × 72
9. Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits 
for the duration of studyparticipation.
10. Willingness of men and women of reproductive potential (defined as following menarche and not postmenopausal 
[and 2 years of non-therapy-induced amenorrhea] or surgically sterile) to observe conventional and highly effective
birth control methods with failure rates of <1% for the duration of treatment and for 6 months following the last dose 
of study treatment; this must include barrier methods such as condom or diaphragm with spermicidal gel. See 
Section 4.1 of this protocol for detailed listing of acceptable methods of birth control. Sperm donation is prohibited 
during the duration of participation on this protocol and for 6 months after the last dose of studydrug.
Exclusion Criteria:
11. Investigational agent or anticancer therapy (including some Chinese traditional medicine with anti-tumor indication 
in label) within 5 half-lives or 14 days, whichever is shorter, prior to planned start of LOXO-305 except therapeutic 
monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of LOXO-305.
In addition, no concurrent systemic anticancer therapy is permitted.
a.
Continuation of certain standard of care anticancer therapies, including hormonal therapy for breast and 
prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications. Refer to
Section 6.3.2 for allowed and Section 6.3.3 for prohibited medications.
12. Major surgery (excluding placement of vascular access or biopsy) within 4 weeks prior to planned start of 
LOXO-305.
13. Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except 
for patients receiving radiation to pelvis, skull or sternum (bone marrow area) or receiving whole brain radiotherapy,
which must be completed at least 4 weeks prior to the first dose of study treatment.
14.Patients requiring therapeutic anticoagulation with warfarin.
15. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events 
(CTCAE [version 5.0]) Grade 2 at the time of starting study treatment except for alopecia or otherwise specified in 
this eligibility criteria.
16. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-
T) therapy within the 60 days prior to planned start of LOXO-305 treatment or with any of the following:
a.
Active graft versus host disease(GVHD);
b.
Cytopenia requiring transfusion support reflecting incomplete blood count recovery post-transplant;
c.
Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity >Grade 
1 from CAR-T therapy;
d.
Ongoing immunosuppressive therapy.
17. Known central nervous system (CNS) involvement by systemic lymphoma. Patients with previous treatment for 
CNS involvement who are neurologically stable (neurological symptoms and CNS imaging are stable and steroid 
dose is stable for 14 days prior to the first dose and no CNS surgery or radiation has been performed for 28 days, 14 
days if stereotactic radiosurgery [SRS]) and without evidence of disease may be eligible and enrolled to Cohort 3 if 
a compelling clinical rationale is provided by the investigator and with documented sponsor approval. Primary CNS 
lymphoma is excluded.
18. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic 
thrombocytopenic purpura [ITP]) where new therapy introduced, or concomitant therapy escalated within the 4
weeks prior to study enrollment is required to maintain adequate blood counts.
19.Significant cardiovascular disease defined as:
a.
Unstable angina, or
b.
History of myocardial infarction within 6 months prior to planned start of LOXO-305, or
c.
Documented left ventricular ejection fraction (LVEF) by any method of ≤45% in the 12 months prior to planned 
start of LOXO-305, assessment of LVEF during screening should be performed in selected patients as 
medically indicated or
d.
Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification (refer 

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 6
L Y 3 5 2 7 7 2 7
t o A p pe n di x G ), or
e.
U n c o ntr olle d or s y m pt o matic arr h yt h mias
2 0. P r ol o n gati on of t he Q T i nter val c orrecte d f or hear t rate ( Q Tc F) > 4 7 0
msec
o n at least 2/ 3 c o nsec uti ve
electr ocar di o gra ms ( E C Gs), a n d mea n Q Tc F > 4 7 0 msec o n all 3 E C Gs, d uri n g Scree ni n g. Q Tc F is calc ulate d usi n g 
Fri dericia’s F or m ula ( Q Tc F): Q Tc F = Q T/( R R 0. 3 3).
a.
C orrecti o n of s us pecte d dr u g -i n d uce d Q Tc F pr ol o n gati o n ca n be atte m pte d at t he in vesti gat o r’s discreti o n a n d 
o nl y  if cli nicall y safe t o d o s o wit h eit her disc o nti n uati o n of t he offe n di n g dr u g o r s witc h t o a n ot her dr u g n ot 
k n o w n t o be ass ociate d wit h Q Tc F pr ol o n gati o n (a ge nts k n o w n t o ca use Q Tc pr ol o n gati on r ef er t o A p pe n di x
H ).
2 1. Patie nts w h o e x perie nce d a maj or blee di n g e ve nt or gra de ≥3 arr h yt h mia o n pri or treat me nt wit h a B T K i n hi bit or.
N O T E:  Maj or blee di n g is defi ne d as blee di n g ha vi n g o n e or m ore of t h e f oll o wi n g feat ures:  pote ntiall y life-
t hreate ni n g blee di n g wit h si g ns or s y m pt o ms of he m o d y na mic c o m pr o mise; blee di n g ass ociate d wit h a decrease i n 
t he he m o gl o bi n le vel of at least 2 g per deciliter; or blee di n g i n a cr itical area or  or ga n (e. g., retr o perit o neal, 
i ntraartic ular, pericar dial, e pi d ural, or i ntracra nial blee di n g or i ntra m usc ular blee di n g wit h c o m part me nt s y n dr o me).
2 2. Acti ve u nc o ntr olle d s yste mic bacterial, viral, f u n gal or parasitic i nfecti o n (e xce pt f or f u n gal nail i nfecti o n), or ot her 
cli nicall y si g nifica nt acti ve disease pr ocess w h ic h i n t he o pi ni o n of t he in vesti gat or a n d t he sp o ns or ma kes it 
u n desira ble f or t he patie nt t o partici pate i n t he trial. Scree ni n g f or c hr o nic c o n diti o ns is n ot re q uire d.
2 3. Patie nts w h o ha ve teste d p ositi ve f or Hu ma n Im m u n o deficie nc y Vir us ( HI V) are e xcl u de d d ue t o p ote ntial dr u g-
dr u g i nteracti o ns bet wee n a nti -retr o viral me dicati o ns a n d L O X O-3 0 5 a n d ris k of o p p ort u nistic i nfecti o ns wit h b ot h 
HI V a n d irre versi ble B T K i n hi bit ors.  For  patie nts wit h u n k n o w n HI V stat us, HI V testi n g will be perf or me d at
Scree ni n g a n d res ult s h o ul d be ne gati ve f or e nr oll me nt .
2 4. Ha ve acti ve He patitis B or C. 
a.
Patie nts wit h detect a ble he patitis B vir us ( H B V) D N A a n d c o ntr olle d disease ma y be per mitte d o n t hera p y 
wit h s p o ns or a p pr oval . C o nc urr e n t viral s u p pressi ve treat me nt will be re q uire d f or patie nts wit h detecta ble 
H B V D N A . Refer t o Secti o n 6. 3. 2 f or all o we d a n d Secti o n 6. 3. 3 f or pr o hi bite d me dicati o ns.
b.
Patie nts wit h hist o r y of he p atitis C vir us ( H C V) i nfecti o n w h o ha ve c o m plete d viral s u p p ressi ve t hera p y a n d 
ha ve a viral l oa d bel o w t he li mit of q ua ntifi cati o n are all o we d.
2 5. Cli nicall y si g nifica nt acti ve mala bs or pti o n s y ndr o me or ot her c o n diti o n s li kel y t o affect gastr oi ntesti nal ( GI) 
a bs or pti o n of t he st u d y dr u g .
2 6. C urre nt treat me nt wit h certai n str o n g c yt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4) i n hi bit ors or i n d ucers (refer t o A p pe n di x I) 
a n d/ or str on g p -gl y c o pr otei n ( P-g p) i n hi bit ors wit hi n 7 da ys bef ore starti n g L O X O- 3 0 5 (refer t o A p pe n di x J).
2 7. Pre g na nc y or lactati o n.
2 8. Acti ve sec o n d mali g na nc y u nless i n re missi o n a n d wit h life e x pecta nc y >2 years a n d wit h d oc u me nt e d sp o ns or 
a p pr o val . Refer t o Pr ot oc ol E xcl usi o n Criteria (Secti o n 4. 2 ) f or e xa m ples of all o we d sec o n d mali g na ncies.
2 9. Pri o r treat me nt wit h L O X O- 3 0 5.
3 0. Patie nts wit h k n o w n h y perse nsiti vit y t o a n y c o m p o ne nt or e xci pie nt of L O X O - 3 0 5.
P L A N N E D S A M P L E SI Z E:
 
I N V E S TI G A TI O N A L P R O D U C T:
L O X O - 3 0 5 will be pr o vi de d as ta blets.  The ta blets will be pr o vi de d t o t he sites f or distri b utio n  to t he patie nt f or 
o ut patie nt a d mi nistrati o n at assi g ne d d ose le vel. D os e is i nte n de d t o be fi xe d (i.e., n ot wei g ht -base d or b o d y s urface 
area [ B S A] -base d).
T R E A T M E N T P R O C E D U R E S:
Patie nts will be gi n L O X O - 3 0 5 o n  C ycle 1 Da y 1 ( C 1 D 1) wit h 2 0 0 m g Q D, a n d c ycle le n gt h will be 2 8 da y s. Patie nts 
will c o nti n ue d osi n g u ntil pr o gr essi ve disease ( P D) as defi ne d b y disease s pecific res p o nse criteria a n d assesse d b y 
i n vesti gat or, u nacce pta ble t o xicit y, or ot her reas o ns f or tr eat me nt disc o nti n uati o n.  Patie nts wit h d oc u me nte d P D ma y 
be all o we d t o c o nti n ue L O X O - 3 0 5 if t he patie nt is t olerati n g st u d y dr u g a n d, i n t he o pi ni o n of t he in vesti gat o r, t he 
patie nt is deri vi n g cli nical be nefit fr o m c o nti n ui n g st u d y treat me nt, a n d c o nti n uati o n of treat me nt is a p pr o ve d b y t h e 
sp o ns or , u ntil t he patie nt gets t he 2 n d P D , u nacce pta ble t o xicit y occ urs or t he i n vesti gat or a grees t hat t he patie nt will 
n o l on ger be nefit fr o m treat me nt. Patie nts c o nti n ui n g L O X O - 3 0 5 treat me nt wit h s p o ns or a p pr o val s ho ul d still f oll o w 
o n -treat me nt re g ular visit a n d rele va nt assess me nt.
S T U D Y A S S E S S M E N T S:
Safet y o bser vati o ns i ncl u de p h ysical a n d ne ur ol o gical e xa mi nati o n, b o d y wei g ht, E C O G sc ore, cli nical a d verse e ve nts 
C CI

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 7
L Y 3 5 2 7 7 2 7
( A Es), la b orat or y varia bles ( he mat ol o g y, ser u m or plas ma c he mistries, a n d uri nal ysis), E CGs a n d vital si g ns.
M C L patie nts i n C o h ort 1 wit h his t or y of or e vi de nce of GI i n v ol ve me nt o n baseli ne assess me nt ma y re q uire a p pr o priate 
u p per a n d/ or l o wer e n d osc o p y pr oce d ure (if it is cli nicall y safe) d uri n g scree ni n g wit h bi o ps y t o d oc u me nt i n v ol ve me nt
at baseli ne , a n d foll o w u p u p per a n d/ o r l o wer e n d osc o p y f or d oc u me ntati o n of c o m plete res p o nse will be re q uire d f or 
t hese patie nts, as a p pr o priate.
Efficac y assess me nts i ncl u de t u m or e val uati o n (ra di ol o gic a n d la b orat or y) e ver y 8 w ee ks be gi n ni n g wit h C ycl e 3 Da y 
1 ( ± 7 da ys) t hr o u g h C ycl e 1 2 Da y  1, t h en ~ e v er y  12 wee ks t hereafter ( ± 2 wee ks) f or 1 year, t he n ~ e ver y 6 c ycles 
( ± 4 wee ks) t h er eafter, c o nsiste nt wit h disease -defi ne d criteria.  An i nitial res p o nse e val uati on ( o pti o nal base d o n cli nical 
i n dicate d) m a y  be c o n d ucte d o n C ycle 2 Da y 1 ( ± 7 d a ys) wit h a c o nfir mat or y res p o nse e val uati o n c o n d ucte d 4 wee ks 
( C ycle 3 D a y  1± 7 da y s) after t he first t u m or e val uati o n, if c o nsiste nt wit h l ocal i nstit uti o n a n d re g ulat or y aut h orit y 
re q uire me nts.  
S ca ns, b o ne m arr o w a n d peri p heral bl o o d sa m ples (w h ere a p plica ble) use d t o assess res p o nse will be c ollecte d t o per mit 
i n de pe n de ntre vie w.
A n E n d of Treat me nt ( E O T) visit wit hi n 7 da ys of t he last d ose of L O X O -3 0 5 or t he decisi o n t o ter mi nate treat me nt is 
re q uire d.
I n a d diti o n, a Safet y F oll o w -u p ( S F U) visit bet wee n 4 a n d 5 wee ks after t he last d ose of st u d y  treat me nt (i.e., 2 8 da ys 
after t he last d ose of st u d y dr u g [ + 7 da ys]) is re q uire d t o deter mi ne t he stat us of a n y u nres ol ve d A Es.
All patie nts will e n ter L o n g -term F oll o w - u p ( L T F U) wit h visits ~ e ver y 3 m o nt hs (± 1 m o nt h ) f or up t o 2 years a n d 
~e ver y 6 m o nt hs ( ± 2 m o nt h ) t hereafter, f or c o nfir mi n g t he res ol uti o n of a n y seri o us a d verse e ve nts ( S A Es), P D if n ot 
occ urri n g o n st u d y, s u bse q ue nt a ntica ncer t hera p y, a n d s ur vi val.  L T F U ma y be c o n d ucte d b y p h o ne if a patie nt u na ble 
t o tra vel t o cli nic.
Patie nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n P D, wit h dra wal of c o nse nt or  initiati o n of a ne w 
a ntica ncer t hera p y, ma y c o nti n ue u n der g oi n g disease assess me nt as a p pr o priate t o hist ol o g y  (as s pecifie d a b o ve) u ntil 
P D, wit h dra wal of c o nse nt, or i nitiati o n of a ne w a ntica ncer t hera p y.
 
 
P K Ti me p oi nts are s pecifie d i n pr ot oc ol Secti o n 7. 2 .
A d diti o nal P K m a y  als o be assesse d w h e n c o nsi dere d necessar y  by t he in vesti gat o r or  the s p o ns or t o u n dersta n d t he 
relati ons hi p bet wee n L O X O -3 0 5 e x p os ure a n d safet y or efficac y.
At st u d y e ntr y, t um or sa m ples (l ym p h n o de/t u m o r bi o ps y or b o ne marr o w) will be o btai ne d fr om patie nts e nr olle d i n 
C o h ort 1 f or disease a n d hist ol o g y c o nfir mati on at ce ntral la b.  G ui da nce is pr o vi de d i n t he La b orat or y Ma n ual a n d
A p pe n di x K o f t he Pr ot oc ol
S T A TI S TI C A L M E T H O D S:
S afet y A n al yses:
T he safet y p o p ulati o n will c o nsist of all e nr olle d patie nts w h o recei ve at least 1 d ose of L O X O -3 0 5. A baseli ne 
meas ure me nt a n d at least 1 la b orat or y or ot her safet y-relate d meas ure me nt o btai ne d after t he start of st u d y dr u g ma y be 
re q uire d f or i ncl usi o n i n t he a nal ysis of a s pecific safet y para meter.
Effic ac y A n al yses:
Patie nts e nr olle d w h o meet t he cr iteria f or t he pr i mar y a nal ysis set ( P A S) will be i ncl u de d i n t he pr i mar y a nal ysis f or
C o h orts 1 a n d 2 , as defi ne d se paratel y i n t he statistical a nal ysis pla n.
O verall res p o nse rate (O R R ) will be assesse d usi n g L u ga n o criteria ( A p pe n di x A ) or I W C L L (A p pe n di x B ) i ncl u di n g 
assess me nt of c o m plete res p o nse wit h
i nc o m plete marr o w 
rec o ver y (C Ri), n o d ular P R ( n P R), a n d P R wit h 
l ym p h oc y t osis ( P R-L) , or I W W M (A p pe n di x C ), as a p pr o priate t o t u m or t ype.
T he esti mate of t he O R R will be
calc ulate d as t he pr o p orti o n of patie nts wit h best o verall res p o nse (B O R ) of P R or better, base d o n I W C L L , P R or better 
base d o n L u ga n o, a n d mi n or res p o nse or  better f or WM base d o n I W W M criteria as deter mi ne d b y I R C a n d b y t h e 
treati n g in vesti gat o r.  T he esti mates of t he O R R will be acc o m pa nie d b y a 2 -si de d 9 5 % c o nfi de nce i nter val ( CI).
Waterfall pl ots will be use d t o de pict gra p hicall y t he ma xi m u m decrease fr o m baseli ne i n t he s u m of pr o d uct dia meters 
( S P D) of tar get lesi o ns.  D ur ati o n o f res p o nse (D O R ), pr o gressi o n -free s ur vi val (P F S ), a n d o verall s ur vi val (O S ) will 
be s u m marize d descri pti vel y f or eac h c o h ort usi n g t he Ka pla n-Meier met h o d.
P h ar m ac o ki netic A n al yses:
Plas ma c o nce ntrati o ns of L O X O - 3 0 5 will be deter mi ne d wit h a vali date d bi o a nal ytical assa y.  The f oll o wi n g P K 
para meters will be calc ulate d fr o m plas ma c o nce ntrati o ns if a p pr o priate: C ma x , T ma x , A U C 0 – t (area u n der t he 
c o nce ntrati o n vers us ti me c ur ve fr o m ti me 0 t o t), a p pare nt oral cleara nce ( C L/ F), a p pare nt v ol u me of distri b uti o n 
( Vz/ F), a n d T1/ 2.
C CI

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Summary statistics will be generated by cohort and across cohorts as appropriate.

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TABLE OF CONTENTS
SYNOPSIS.............................................................................................................................. 2
TABLE OF CONTENTS ........................................................................................................ 9
LIST OF TABLES ................................................................................................................ 12
LIST OF FIGURES............................................................................................................... 13
LIST OF APPENDICES ....................................................................................................... 14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS............................................ 15
1.
INTRODUCTION..................................................................................................... 19
1.1
BTK-Dependent Malignancies and Current Treatment Options ...................... 19
1.2
LOXO-305..................................................................................................... 23
1.2.1
Chemistry and Description.................................................................. 23
1.2.2
Nonclinical ......................................................................................... 23
1.2.3
Clinical Experience............................................................................. 26
1.2.4
Determination of Recommended Phase 2 Dose................................... 28
1.3
Anticipated Risks ........................................................................................... 29
1.3.1
Anticipated Risks of LOXO-305 from Animal Studies........................ 30
1.3.2
Safety Experience Reported with Other BTK Inhibitors...................... 32
1.4
Benefit/Risk ................................................................................................... 32
2.
STUDY OBJECTIVES AND ENDPOINTS.............................................................. 34
3.
INVESTIGATIONAL PLAN .................................................................................... 35
3.1
Study Design.................................................................................................. 35
3.2
General Treatment Procedures........................................................................ 36
4.
SELECTION OF STUDY POPULATION ................................................................ 38
4.1
Inclusion Criteria............................................................................................ 38
4.2
Exclusion Criteria........................................................................................... 40
5.
ENROLLMENT PROCEDURES.............................................................................. 43
6.
TREATMENTS AND ADMINISTRATION ............................................................. 44
6.1
Investigational Product................................................................................... 44
6.2
LOXO-305 Administration............................................................................. 44
6.2.1
General Dosing Instructions................................................................ 44
6.2.2
Dose Delays/Modifications................................................................. 45
6.3
Prior and Concomitant Medications................................................................ 46
6.3.1
General............................................................................................... 46

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6.3.2
Allowed Concomitant Medications..................................................... 46
6.3.3
Prohibited Concomitant Medications .................................................. 47
6.3.4
Contraindications................................................................................ 47
6.4
Duration of Treatment.................................................................................... 48
6.5
Discontinuation of Study Intervention ............................................................ 48
6.5.1
Discontinuation of Inadvertently Enrolled Patients.............................. 49
6.6
Discontinuation from Study............................................................................ 49
6.7
Lost to Follow-Up.......................................................................................... 49
7.
STUDY PROCEDURES AND ASSESSMENTS ...................................................... 51
7.1
Study Assessments......................................................................................... 59
7.1.1
Informed Consent ............................................................................... 59
7.1.2
Screening............................................................................................ 59
7.1.3
Enrollment.......................................................................................... 59
7.1.4
Medical and Surgical History, and Demographics............................... 59
7.1.5
Physical Examination ......................................................................... 59
7.1.6
Eastern Cooperative Oncology Group Performance Status.................. 60
7.1.7
Vital Signs.......................................................................................... 60
7.1.8
Electrocardiograms............................................................................. 60
7.1.9
Laboratory Tests................................................................................. 61
7.2
Pharmacokinetics ........................................................................................... 63
7.3
Telephone Follow-up ..................................................................................... 63
7.4
Central Tumor Sample Submission (Peripheral Blood, Bone Marrow, Tissue)63
7.5
Pathology and Molecular Reports................................................................... 65
7.6
Bone Marrow Aspirate and Biopsy................................................................. 65
7.7
Gastrointestinal Endoscopy ............................................................................ 65
7.8
Radiologic Disease Assessment...................................................................... 65
7.9
Survival Status ............................................................................................... 66
7.10
Study Drug and Dosing Diary ........................................................................ 66
7.11
Concomitant Medication ................................................................................ 67
7.12
Adverse Events/Serious Adverse Events......................................................... 67
7.13
Patient-reported Outcomes (PRO) Assessments.............................................. 67
7.14
Central Collection of Radiographic Studies and Samples................................ 67
7.15
End of Treatment ........................................................................................... 68
7.16
Safety Follow-up............................................................................................ 68

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7.17
Long-Term Follow-up.................................................................................... 68
8.
STATISTICAL CONSIDERATIONS........................................................................ 69
8.1
Analysis Populations...................................................................................... 69
8.1.1
Safety Population................................................................................ 69
8.1.2
Primary Analysis Set .......................................................................... 69
8.2
Determination of Sample Size ........................................................................ 69
8.3
Statistical Analyses ........................................................................................ 70
8.3.1
Demographics and Baseline Characteristics ........................................ 70
8.3.2
Safety Analyses .................................................................................. 70
8.3.3
Efficacy Analyses............................................................................... 71
8.3.4
Pharmacokinetic Analyses .................................................................. 72
8.3.5
Primary Analysis ................................................................................ 72
9.
ADVERSE EVENTS................................................................................................. 73
9.1
Serious Adverse Event Reporting................................................................... 73
9.2
Hepatic Safety Monitoring ............................................................................. 75
9.3
Serious Adverse Event Follow-up .................................................................. 76
9.4
Pregnancy Reporting ...................................................................................... 76
10.
STUDY ADMINISTRATION................................................................................... 77
10.1
Regulatory and Ethical Considerations ........................................................... 77
10.1.1 Regulatory Authority Approval........................................................... 77
10.1.2 Ethics Approval.................................................................................. 77
10.1.3 Patient Informed Consent.................................................................... 77
10.1.4 Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee................................................. 78
10.1.5 Sponsor Safety Reporting to Regulatory Authorities........................... 78
10.2
Data Management .......................................................................................... 79
10.3
Study Monitoring ........................................................................................... 79
10.4
Termination.................................................................................................... 79
10.5
Records Retention.......................................................................................... 80
10.6
Confidentiality of Information........................................................................ 80
11.
APPENDICES........................................................................................................... 81
12.
REFERENCES........................................................................................................ 133

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LIST OF TABLES
Table 1.1
Demographics and Baseline Characteristics of LOXO-BTK-18001 Study 
Population........................................................................................................... 27
Table 2.1
Objectives and Endpoints .................................................................................... 34
Table 3.1
Chemoimmunotherapy for MCL ......................................................................... 36
Table 6.1
Suggested Dose Reduction Levels for LOXO-305 for Toxicity Management ...... 46
Table 7.1
Schedule of Assessments..................................................................................... 52
Table 7.2
Schedule of PK Assessments............................................................................... 58
Table 8.1
Lower Bounds of 2-sided Exact 95% CI Based on Varying Sample Size and 
Observed ORR .................................................................................................... 70
Table 11.1 Lugano Classification of Response...................................................................... 82
Table 11.2 Response Definition after Treatment of CLL/SLL Patients .................................. 85
Table 11.3 Waldenström Macroglobulinemia Response Assessment Criteria......................... 87
Table 11.4 Classes of Heart Failure....................................................................................... 91
Table 11.5 Examples of Agents Known to Cause QTc Prolongation ..................................... 92
Table 11.6 Inhibitors of CYP3A4.......................................................................................... 93
Table 11.7 Inducers of CYP3A4 ........................................................................................... 94
Table 11.8 Examples of Strong P-gp Inhibitors ..................................................................... 95
Table 11.9 Guidelines for Patient Sample Collection for Central Analysis ............................ 96
Table 11.10
Eastern Cooperative Oncology Group Performance Scale.............................. 98
Table 11.11
Liver Evaluation Testing ............................................................................. 100

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LIST OF FIGURES
Figure 3.1
Study Schema...................................................................................................... 36

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LIST OF APPENDICES
Appendix A
Lugano Classification of Response in Non-Hodgkin Lymphoma................... 82
Appendix B
Chronic Lymphocytic Leukemia Response Assessment (IWCLL)................. 85
Appendix C
Waldenström Macroglobulinemia Response Assessment (IWWM) ............... 87
Appendix D
Treatment Failure and Intolerance ................................................................. 88
Appendix E
Prior BTK Inhibitors ..................................................................................... 89
Appendix F
Indication for Treatment of CLL/SLL............................................................ 90
Appendix G
New York Heart Association (NYHA) Functional Classification................... 91
Appendix H
Examples of Agents Known to Cause QTc Prolongation ............................... 92
Appendix I
Inhibitors and Inducers of CYP3A4............................................................... 93
Appendix J
P-gp inhibitors............................................................................................... 95
Appendix K
Guidelines for Patient Sample Collection for Central Analysis ...................... 96
Appendix L
Eastern Cooperative Oncology Group Performance Scale Table.................... 98
Appendix M
Patient Reported Outcome (PRO) Assessments ............................................. 99
Appendix N
Liver Safety: Suggested Actions and Follow-Up Assessments..................... 100
Appendix O
Provisions for Changes in Study Conduct During Exceptional Circumstances
................................................................................................................... 102
Appendix P
Protocol JZNJ Amendment (b) Summary: A Phase 2 Study of Oral LOXO-305 
in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small 
Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL). 106

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or Term
Definition
AE
adverse event
AIHA
autoimmune hemolytic anemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the concentration versus time curve
AUC0-24
area under the concentration versus time curve from time 0 to 24 hours
AUC0-t
area under the concentration versus time curve from time 0 to t
BBB
bundle branch block
BCR
B cell receptor
BID
twice daily
BLC2
B-cell lymphoma 2
BMX
BMX tyrosine kinase
BOR
best overall response
BUN
blood urea nitrogen
BSA
body surface area
BTK
Bruton’s tyrosine kinase
BTKi
Bruton’s tyrosine kinase inhibitor
C1D1
Cycle 1 Day 1
C481
cysteine residue at position 481
CAR-T
chimeric antigen receptor-modified T cells
CHO
Chinese Hamster Ovary cells
CI
confidence interval
CL/F
apparent oral clearance of drug
CLL
chronic lymphocytic leukemia
Cmax
maximum drug concentration
Cmin
minimum drug concentration
CMV
cytomegalovirus
CNS
central nervous system
CR
complete response
CRF
case report form
CRi
complete response with incomplete marrow recovery
CRP
clinical research physician
CYP3A4
cytochrome P450 3A4
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAG
diacyl glycerol
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity

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Abbreviation or Term
Definition
DNA
deoxyribonucleic acid
DOR
duration of response
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EOT
End of Treatment
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of 
EORTC IL-63
European Organization for Research and Treatment of Cancer Items Library 
ERK
extracellular signal-regulated kinase
FDA
Food and Drug Administration
FL
follicular lymphoma
FLC
free light chain
FOB
functional observational battery
GCP
Good Clinical Practices
GI
gastrointestinal
GLP
Good Laboratory Practice
GnRH
gonadotropin-releasing hormone
GVHD
graft versus host disease
Hb
hemoglobin
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDV
hepatitis D virus
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HPBL
human peripheral blood lymphocytes
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
IC90
90% inhibitory concentration
ICF
informed consent form
ICH
International Council for Harmonisation
ICH GCP
International Council for Harmonisation-Good Clinical Practices
IEC
Independent Ethics Committee
INR
international normalized ratio
IP3
inositol 3-phosphate
IRB
Institutional Review Board
IRC
Independent Review Committee
ITK
IL2-inducible T-cell kinase
ITP
idiopathic thrombocytopenic purpura

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Abbreviation or Term
Definition
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
Intravenous
Km
Michaelis constant
LDH
lactate dehydrogenase
LDi
longest diameter
LDT
lymphocyte doubling time
LHRH
luteinizing hormone-releasing hormone
LMA
locomotor activity
LOXO-305
investigational product
LTFU
Long-term Follow-up
LVEF
left ventricular ejection fraction
LYN
LYN tyrosine kinase
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
MR
minor response
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MZL
marginal zone lymphoma
NCI CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse 
NFAT
nuclear factor of activated T cells
NF-κB
nuclear factor kappa-light-chain-enhancer of activated B cells
NHL
non-Hodgkin lymphoma
nPR
nodular PR
ORR
overall response rate
OS
overall survival
PAS
primary analysis set
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
P-gp
p-glycoprotein
PI3K
PI3-kinase
PIP3
phosphatidylinositol 3-phosphate
PK
pharmacokinetic
PKC
protein kinase C
PLCg2
phospholipase C gamma 2
PR
partial response
PR-L
PR with lymphocytosis
PRO
patient reported outcome

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Abbreviation or Term
Definition
PT
prothrombin time
QD
once daily
QTcF
QT interval corrected for heart rate (Fridericia's formula)
RBC
red blood cell
RNA
ribonucleic acid
R/R
relapsed/refractory
RT
Richter’s transformation
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCT
stem cell transplant
SD
stable disease
SDD
spray-dried dispersion
SERDs
selective estrogen receptor degraders
SERMs
selective estrogen receptor modulators
SFU
Safety Follow-up
SLL
small lymphocytic lymphoma
SPD
sum of product diameters
SPEP
serum protein electrophoresis
SRS
stereotactic radiosurgery
SUSARs
suspected unexpected serious adverse reactions
SYK
spleen associated tyrosine kinase
T1/2
terminal elimination half-life
TBL
Total bilirubin
TEAE
treatment-emergent adverse event
TEC
Tec kinase
TLS
tumor lysis syndrome
Tmax
time to maximum plasma concentration
TXK
TXK tyrosine kinase
ULN
upper limit of normal
VGPR
very good partial response
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WM
Waldenström macroglobulinemia
Xid
X-linked immunodeficiency
XLA
X-linked agammaglobulinemia
Y551
tyrosine residue 551

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1. INTRODUCTION
1.1
BTK-Dependent Malignancies and Current Treatment Options
Bruton’s Tyrosine Kinase (BTK) is a member of the Tec kinase (TEC) family of non-receptor 
tyrosine kinases (which includes BTK, IL2-inducible T-cell kinase [ITK], TEC, TXK tyrosine 
kinase [TXK], and BMX tyrosine kinase [BMX]) and a key component of the B cell receptor 
(BCR) signaling complex. BTK also plays a critical role in the proliferation and survival of 
diverse B cell malignancies.
BTK inactivating mutations were originally identified as the cause of X-linked 
immunodeficiency (Xid) in mice (Rawlings et al. 1993, Thomas et al. 1993) and X-linked 
agammaglobulinemia (XLA) in humans (Vetrie et al. 1993).  XLA is a rare, X-linked recessive 
disorder that causes severe bacterial infections in affected boys due to a complete absence of 
functional B lymphocytes and antibodies (Hendriks et al. 2011). Lifelong treatment with 
antibiotic prophylaxis and intravenous (IV) and/or subcutaneous (SC) immunoglobulins can 
prevent infection and lead to normal life expectancy.
In normal B cells, antigen binding to the BCR leads to activation of the upstream kinases LYN 
tyrosine kinase (LYN) and spleen associated tyrosine kinase (SYK), recruitment of PI3-kinase 
(PI3K), generation of the second messenger phosphatidylinositol 3-phosphate (PIP3) and 
PIP3-dependent recruitment of BTK to the plasma membrane. LYN and SYK-mediated 
phosphorylation of BTK on tyrosine residue 551 (Y551) stimulates the kinase activity of BTK, 
leading to autophosphorylation on Y223 and phosphorylation-dependent activation of the 
critical downstream signaling effector phospholipase C gamma 2 (PLCg2). PLCg2-mediated 
generation of second messengers inositol 3-phosphate (IP3) and diacyl glycerol (DAG) induces 
the activation of several critical signaling effectors (nuclear factor of activated T cells [NFAT], 
mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK], protein 
kinase C [PKC], nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kB]) which 
results in increased proliferation and survival.
BTK expression is restricted to a subset of B cells and myeloid cells, and in malignancies 
thought to derive from them, including chronic lymphocytic leukemia (CLL, related to naïve B 
cells), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL, each related to 
germinal center B cells) and Waldenström macroglobulinemia (WM, plasma cells).  Consistent 
with a critical survival role for BTK in these malignancies, BTK deficiency abrogates tumor 
formation in CLL mouse models (Kil et al. 2013), and treatment of primary, patient-derived 
CLL, MCL and WM cells with the irreversible BTK inhibitor ibrutinib reduces their viability, 
adhesion and migration (Herman et al. 2011, Chang et al. 2013, Yang et al. 2013).

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Covalent BTK inhibitors inhibit BTK by binding to the adenosine triphosphate (ATP) pocket of 
the enzyme and forming an irreversible, covalent bond with the cysteine residue at position 481 
(C481) in the BTK enzyme. Covalent ligation of BTK inhibits its kinase activity, induces BTK 
degradation and causes potent and prolonged BTK target engagement and inhibition in patients 
(Byrd et al. 2013). Three covalent BTK inhibitors have been approved globally for the 
treatment of patients with B cell malignancies, including ibrutinib, acalabrutinib, and 
zanubrutinib. These drugs have altered the treatment paradigms of many B-cell malignancies, 
including CLL/SLL, relapsed/refractory (R/R) MCL, Waldenström macroglobulinemia (WM), 
and marginal zone lymphoma (MZL). Ibrutinib is the only approved BTK inhibitor in China for 
patients with R/R MCL, CLL/SLL, or WM.  
Importantly, however, long-term efficacy is ultimately limited by toxicity and acquired 
resistance. In R/R CLL, although initial response rates to ibrutinib are high, rates of treatment 
discontinuation are also high (~40%) with extended follow-up (Woyach et al. 2017, Mato et al. 
2018). The most common reasons for treatment discontinuation in CLL are adverse events 
(AEs) in ~50% to 60%, progression in ~20% to 30%, and Richter’s transformation (RT) in ~5%
to 15% of patients. Toxicities of ibrutinib that lead to dose interruptions and treatment 
discontinuation include arthralgia, atrial fibrillation, rash, cytopenias, infection, pneumonitis, 
bleeding and diarrhea (Mato et al. 2018). These toxicities have been attributed to both on-target 
BTK inhibition and off-target inhibition of other kinases such as TEC (McMullen et al. 2014,
Kamel et al. 2015). A retrospective analysis of the RESONATE trial indicated worse 
progression-free survival (PFS) in patients with R/R CLL with lower ibrutinib dose intensity and 
dose interruptions lasting for longer than 7 days, suggesting that treatment interruptions for 
toxicity can adversely impact long-term outcomes (Barr et al. 2017).
Recent analysis of primary CLL samples from patients with relapsed CLL who responded to, 
but then ultimately progressed on ibrutinib, has uncovered 2 primary mechanisms of acquired 
resistance: substitution at cysteine 481 (481), primarily with a serine residue (i.e., C481S) in the 
majority (67%) of patients, which prevent irreversible binding of covalent BTK inhibitors to 
BTK; activating mutations in PLCG2, a critical signaling effector downstream of BTK in 13%; 
and less commonly, both mutations occurring in the same patient (7%) (Woyach et al. 2017). 
These frequencies have been validated in more recent studies (Bonfiglio et al. 2018). Other 
studies have uncovered C481 substitution mutations in WM and MCL, indicating that C481 
substitutions represent a common mechanism of “on target” resistance to irreversible BTK 
inhibitors in patients (Chiron et al. 2014, Xu et al. 2017).
There are no proven available therapies for patients with B-cell malignant lymphoma (especially 
MCL and CLL/SLL) who failed BTK inhibitors due to the development of resistance.
Management of MCL
MCL is a rare and aggressive subtype of non-Hodgkin lymphoma (NHL). Young and fit 
patients typically receive induction chemo-immunotherapy, followed by high-dose 
chemotherapy with autologous stem cell salvage, and finally rituximab maintenance. In 
transplant ineligible patients, induction chemo-immunotherapy followed by rituximab 
maintenance is an accepted alternate approach. Ultimately, none of these approaches are 
considered curative, and relapse is nearly universal.

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Ibrutinib has been approved in China as salvage therapy for patients progressing following 
upfront chemo-immunotherapy, with or without transplant. A pooled analysis from 3 ibrutinib 
studies in previously treated MCL patients involving 370 relapsed MCL patients reported a 
mature median PFS of 12.5 months (Rule et al. 2019).  
Outcomes in MCL patients following progression on BTK inhibitors are extremely poor, and 
there are no proven available therapies.  No prospective trials have evaluated investigational 
agents in the post-BTK treatment setting but retrospective analyses have generated response 
rates to salvage therapies ranging from 30% to 55% across multiple studies, and characterized 
by a response duration that tends to be short, with PFS of approximately 3 months and overall 
survival (OS) of 8 to 9 months (Cheah et al. 2015, Martin et al. 2016, Epperla et al. 2017, Eyre 
et al. 2019).  Chimeric antigen receptor-modified T cells (CAR-T) cell therapy for MCL 
patients who relapsed including after prior BTK inhibitor has recently gained approval in the 
United States based on single-arm phase 2 data (Wang et al. 2020).  However, CAR-T therapy is 
still under development in China, and cell therapy products have significant barriers to access 
due to process, ethics, safety, and financial concerns, as well as the fact that the long-term 
remission of CAR-T therapies has yet to be verified. In summary, new effective and safe 
therapies are urgently needed for these patients. 
Management of CLL/SLL
For newly diagnosed CLL/SLL, BTK inhibitors (ibrutinib or acalabrutinib), B-cell lymphoma 2 
(BCL2) inhibitors (venetoclax), CD20 monoclonal antibodies and chemo-immunotherapy have 
been recommended as standard treatments internationally. Increasingly BTK inhibitors are 
becoming the preferred first-line therapy due to the desire to avoid the intensity of chemo-
immunotherapy or inpatient monitoring for tumor lysis syndrome (TLS) (often required with 
initiation of venetoclax). In addition, patients find the favorable risk-benefit profile of BTK 
inhibitors combined with the convenience of oral dosing compelling. First-line BTK inhibitor 
use has meaningfully improved PFS and OS compared to chemo-immunotherapy (Shanafelt et 
al. 2019). Importantly, however, these therapies are not curative and patients eventually relapse.
Following progression on BTK inhibitors, median OS in one recent study was only 22.7 months, 
demonstrating an ongoing unmet need for this population (Woyach et al. 2017).
Following treatment with a BTK inhibitor, available approved non-chemo-immunotherapy 
based treatment options include a BCL2 inhibitor (venetoclax) and PI3K inhibitors (idelalisib or 
duvelisib). Of note, studies used to support these regulatory approvals were conducted in 
patients who were almost exclusively BTK inhibitor naïve. For this reason, the true efficacy of 
these options after a BTK inhibitor remains investigational. Therefore, while some post-
marketing studies in BTK inhibitor-treated patients have been conducted with these agents, to 
the sponsor’s knowledge these data have not been reviewed by regulatory authorities and thus 
are not incorporated into existing prescribing information.
Venetoclax’s indications are line-agnostic and thus technically include BTK-treated patients. 
However, the use of venetoclax is associated with several significant risks, most notably TLS. 
Nearly 70% of CLL patients initiating venetoclax meet medium or high-risk criteria (Davids et 
al. 2018, Jones et al. 2018). These patients require prolonged dose titration and intensive 
multiday monitoring as an outpatient (medium-risk patients) or inpatient (high- risk patients). 

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These safety precautions and monitoring scheme have likely limited patient access and can be 
challenging to implement, or even entirely impractical as in the case of oncologists without 
inpatient admitting privileges. 
Another therapeutic option, PI3K inhibitors (idelalisib, duvelisib), also have important caveats 
which impact their clinical use. Specifically, both PI3K inhibitors carry black box safety 
concerns which factor into the risk-benefit determination of prescribing physicians, especially in 
the post-BTK setting. Important risks include infection, colitis, hepatitis, pneumonitis, skin 
toxicity and intestinal perforation. For these reasons, PI3K inhibitors are typically reserved for 
patients who have already exhausted alternative BTK- and BCL2- based therapies. Moreover, 
the efficacy of these agents was established in BTK naïve patients, raising questions regarding 
the applicability of these data in real world practice.
Indeed, post-marketing studies of these agents have reported poor outcomes in patients with 
prior exposure to BTK and/or BCL inhibitors. For example, one retrospective, multicenter 
study reported an overall response rate of only 28% (all partial responses) with idelalisib use 
following BTK inhibitor therapy (Mato et al. 2016), in contrast to the 84% overall response rate 
(ORR) reported in the package insert for idelalisib administered in combination with rituximab 
(Zydelig (idelalisib) USPI).
Despite the perception that novel drug therapies are more broadly available for all settings of 
disease, it is common that patients do not receive all classes of agents targeting the BCR 
pathway during the overall treatment course.  Using data available from an oncology physician-
based panel chart review study representing 485 practice settings across the United States, the 
Applicant queried CLL treatment sequence of BTKi, PI3Ki and BCL2 for utilization in 1st, 2nd, 
and 3rd line therapy during the 12-month time period ending 31 December 2019.  For patients 
receiving ≥2 lines of therapy the data show that only <4% (497/14200) of patients receive 
treatment with all classes of agents targeting the BCR pathway.  These data suggest that the 
standard sequential monotherapy approach to treatment is influenced by several factors 
including drug toxicity, patient preference, underlying disease attributes, and treatment setting 
and the evolution of recent data will result in the incorporation of targeted agents earlier in the 
treatment of CLL/SLL with fewer salvage options available earlier in the treatment sequence.  
In China, ibrutinib and chemo-immunotherapy are the standard of care for newly diagnosed 
CLL/SLL patients. However, after disease progression while on ibrutinib, there is no available 
proven choice. A phase 2 study has been initiated to evaluate the efficacy of BCL2 inhibitor 
(Venetoclax) as monotherapy for previously treated del(17p) CLL/SLL patients and was 
included in the new drug application for R/R CLL early this year. Several PI3K inhibitors are 
still under development, and Venetoclax doesn’t have much experience in the BTK failure 
population. Thus, recommendation for previously treated CLL/SLL patients is still to join 
clinical trials.
In summary, for patients with heavily-treated MCL and CLL/SLL who have received a prior 
BTK inhibitor, there is a significant unmet clinical need to identify new targeted therapies that 
potently and rapidly inhibit BTK in susceptible tumors, while sparing the inhibition of other off-
target kinases and non-kinase that contribute to significant toxicity.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 2 3
L Y 3 5 2 7 7 2 7
1. 2
L O X O - 3 0 5
A s u m mar y  of t he pr o perties, a n d n o ncli nical a n d cli nical fi n di n gs of L O X O -3 0 5 i s pr o vid e d i n 
Secti o n s 1. 2. 1 t o 1. 2. 3 . A d dit i onal i nf or mat i on o n t he n o ncli nical p har mac o l og y , 
p har mac o ki net ics ( P Ks) a n d t o xicity of  L O X O-3 0 5 is pr o vi de d i n t he L O X O -3 0 5 I n vest i gat or’s 
Br oc h ure (I B).
1. 2. 1
C he mistry a n d Descri pti o n
L O X O -3 0 5 i s a s mall mol ec ule t hat bi n ds t o t he A T P site of t he B T K ki nase, pre ve nts A T P 
fr om bi n di n g, a n d i n hi bits B T K’s ki nase act i vity.  T here i s n o e vide nce of c o vale nt or 
irre versi ble bi n di n g.
1. 2. 2
N o ncli nic al
T he p har mac o l og y , P K, a n d t o xic o l og y  pr o gra ms were desi g ne d t o c haracterize t he n o ncli nical 
efficac y, dis p ositio n, a n d safety of  LO X O - 3 0 5 a n d t o e na ble selecti on of  an a p pr o priate starti n g 
d ose f or a p hase 2 cli nical st u d y . T hese are descri be d i n detail i n t he L O X O -3 0 5 I B.

Pri mar y P h ar m ac o d y na mics
L O X O -3 0 5 ca uses p ote nt d ose -de pe n de nt i n hi bit i on of B T K ki nase acti vit y a n d t u m or gr o wt h i n 
m ult i ple, bi ol ogi call y rele va nt B T K-de pe n de nt m o del s yste ms i n vitr o a n d i n vi v o, i ncl u d i n g 
B- cell l y m p h o ma cell li nes a n d e n gi neere d cell li nes.
L O X O -3 0 5 i n hi bite d t he e nz y mat ic 
acti vit y of  B T K a n d B T K C 4 8 1 S i n t he prese nce of A T P at t he Km c o nce ntratio n wi t h 5 0 % 
i n hi bit or y c o nce ntratio n ( I C5 0 ) val ues  
 a n d was m ore t ha n t wice as p ote nt o n B T K C 4 8 1 S.
L O X O - 3 0 5 i n hi bite d B T K a n d B T K C 4 8 1 S cell ular acti vity i ncl u di n g a ut o-p h os p h or ylat i on,
B T K -de pe n de nt pr oliferati o n, a n d acti vat i on of h u ma n B -cells wit h si milar, l o w na n o m o lar 
p ote nc y . L O X O -3 0 5 si g nifica nt l y i n hi bite d t he gr o wt h of B T K-de pe n de nt t u m ors fr o m 2
h u ma n l y m p h o ma li nes ( O CI-L y 1 0 a n d T M D 8) i m pla nte d i nt o i m m u n o deficie nt mice c o m pare d 
t o ve hicle-treate d mice. L O X O -3 0 5 was well -t olerate d b y t he mice i n t he t u m or xe n o graft 
m o d el s.
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
Sec o n dar y  P har mac o d y na mics
L O X O - 3 0 5 at c o nce ntrati o ns pre dicte d t o be ac hie ve d i n h u ma ns is n ot e x pecte d t o ha ve a 
sig nifica nt effect o n a ra n ge of n o n -B T K tar gets a n d rece pt ors.
L O X O -3 0 5 was m ore t ha n 
3 0 0- f ol d selecti ve f or B T K vers us 9 8 % of 3 7 0 n o n-B T K ki nases teste d i n a n e xte nsi ve i n vitr o 
ki nase acti vit y scree n. T his hi g h de gree of select i vity was mai ntai ne d i n a d dit i on al  e nz y me a n d 
cell assa ys. L O X O-3 0 5 was at l east 7 0-f ol d selecti ve f or B T K vers us 9 8 % of 1 8 0 n o n- B T K 
ki nases scree ne d i n li ve h u ma n peri p heral bl o o d m o n o n uclear cells ( P B M Cs) usi n g 
c he m o pr ote o mics met h o ds. I n a d diti on, L O X O -3 0 5 e x hi bit e d n o sig nifica nt tar get i n hi bit i on i n 
a n assa y pa nel o f 4 4 n o n -ki nase rece pt ors a n d e nz y mes.

P har mac o ki net ics
L O X O -3 0 5 has hi g h per mea bilit y i n vitr o, b ut lo w a q ue o us s ol u bilit y.  T o re d uce t he varia bilit y 
i n oral a bs or ptio n, a s pra y -dri e d dis persi o n ( S D D) ta blet f or m ulat i on was de vel o pe d t hat s h o ws 
c o nsiste nt oral bi oa vaila bilit y 
  T he 
bi oa vaila bilit y of  t he S D D f or mulat i on was als o n ot de pe n de nt o n fee di n g state i n d o gs.  T he 
S D D ta blet f or m ulat i on has bee n use d f or h u ma n d osi n g.
L O X O -3 0 5 was m eta b o lize d sl o wl y b y h u ma n micr os o mal fract i ons a n d he pat oc y tes.  T he l o w 
rates of meta b olis m i n b ot h t hese h u ma n i n vitr o s yste ms s u g gest t hat L O X O- 3 0 5 will ha ve l o w 
cleara nce i n h u ma ns. I n vitr o data wit h cl one d e x presse d c y t oc hr o me P 4 5 0 e nz y mes a n d h u ma n 
li ver micr os o mes i n dicate t hat L O X O- 3 0 5 a p pears t o be meta b o lize d b y c yt oc hr ome P 4 5 0
( C Y P 4 5 0) 3 A 4 ( C Y P 3 A 4).
T here was ver y litt le meta b o lis m of L O X O-3 0 5 i n h u ma n he pat oc y tes a n d t he o nl y meta b olite 
detecte d was a gl uc ur o ni de of L O X O -3 0 5. T he gl uc ur o ni de f or me d b y t he h u ma n he pat oc y tes 
was als o f or me d b y rat a n d d o g he pat oc y tes, s u p p ortin g t he use of rat a n d d o g f or n o ncli nical 
safety assess me nt.
Re nal cleara nce of L O X O -3 0 5 i n male a n d fe male rats was ne gli gi ble. N o  re nal cleara nce data 
are a vaila ble i n ot her s pecies, b ut t hi s pat h wa y is ofte n c o nser ve d acr oss s pecies a n d t heref ore, 
n o re nal cleara nce is e x pecte d i n h u ma ns.

Dr u g I nteracti o ns
L O X O -3 0 5 s h o we d n o detecta ble i n hi bit i on of C Y P 1 A 2, C Y P 2 B 6, C Y P 2 C 1 9 a n d C Y P 2 D 6, 
a n d wea k i n hi bit i on of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 3 A 4 wi t h Ki val ues ra n gi n g fr o m 1 1. 7 t o 
2 2. 8 μ M i n h u ma n li ver micr os o mes. After pre -i nc u bati on of micr os o mes wit h L O X O - 3 0 5 a n d 
nic oti na mi de a de ni ne di n ucle oti de p h os p hate ( N A D P H) f or 3 0 mi n utes pri or t o a d dit i on of  
C Y P 4 5 0 pr o be s u bstrate, t he C Y P 3 A 4 i n hi bit o r y p ote nc y of L O X O-3 0 5 was i ncrease d,
s u g gesti n g t he p ote ntial f or ti me-de pe n de nt i n hi bit i on of C Y P 3 A 4. F urt her ki netic e val uati o n
c o nfir me d t hat L O X O-3 0 5 is a ti me de pe n de nt i n hi bit or of C Y P 3 A 4 wit h a K i val ue of
4. 7 0 ± 1. 2 0 μ M a n d a k i nact val ue of 2. 4 4 ± 0. 1 5 h - 1 res ultin g i n Cl i n a ct val ues of 8. 6 4 mi n - 1 m M - 1.
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L Y 3 5 2 7 7 2 7
I n a n i n vitr o he pat oc yte assa y, L O X O-3 0 5 i n d uce d m R N A f or C Y P 3 A 4, C Y P 3 A 5, C Y P 2 B 6, 
a n d C Y P 2 C 1 9. F or b ot h C Y P 2 B 6 a n d C Y P 2 C 1 9 a n i ncrease i n acti vit y was see n. F or 
C Y P 3 A 4, L O X O -3 0 5 di d n ot ca use a n i ncrease i n acti vity,  li kel y d ue t o c o nc urre nt i n hi biti on of 
C Y P 3 A 4 b y  LO X O -3 0 5. L O X O -3 0 5 ca use d a decrease i n m R N A f or C Y P 1 A 2 b ut di d n ot l ea d 
t o a re d ucti o n of C Y P 1 A 2 acti vity. I n t he st u d y, C Y P 2 D 6, C Y P 2 C 8 a n d C Y P 2 C 9 m R N A were 
n ot i n d uce d.
I n vitr o L O XO- 3 0 5 i n hi bite d P -g p, B C R P, M A T E 1, a n d M A T E 2 K. L O X O -3 0 5 di d n ot i n hi bit 
O A T 1 a n d wea kl y i n hi bit e d O A T P 1 B 1, O A T P 1 B 3, O C T 1, O C T 2, O A T 3, a n d B S E P.

S af et y P har mac o l og y
Car di ac safet y was e val uate d i n a G o o d La borat or y  Pr a ctice ( G L P) i n vitr o assa y for h u ma n 
et her - à-g o -g o relate d ge ne ( h E R G ) acti vit y,  i n a G L P i n vi v o st u d y  in c o nsci o us tele metr y -
i nstr u me nte d d o gs, a n d i n a G L P 2 8 -da y re peat -d ose t o xi c o l og y  st u d y ( wit h electr ocar di o gra m 
[E C G ] m o nit ori n g a n d bl o o d press ure meas ure me nts) i n d o gs. L O X O -3 0 5 ha d a n h E R G I C 5 0
val ue of 3 2 µ M, 
 T here 
were n o L O X O - 3 0 5-relate d c ha n ges i n a n y car di o vasc ular e n d p oi nts i ncl u di n g Q Tc at d oses u p 
t o 6 0 mg/ k g i n t he G L P car di o vasc ular st u d y  in t he c o nsci o us d o g s. T he C ma x f or t his d ose was 
1 0 0 0 0 n g/ m L 
F urt her m ore, t here were n o L O X O - 3 0 5-
r elate d a b n or malitie s i n r h yth m or wa vef or m m or p h o l og y  base d o n c o mparis o n of pre -d ose a n d 
p ost d ose E C G rec or di n gs. Mea n Q Tc i nter val was statist icall y si g nifica ntl y pr ol on ge d ( + 6 %; 
+ 1 5 m sec) i n males a d mi nistere d 3 0/ 1 0 m g/ k g/ d ose BI D c o m pare d wit h c o ntr ols. T he 
pr ol o n gati o n i n Q Tc was bel o w t he 1 0 % i ncrease or t he t hres h ol d re p orte d f or ca ni nes e x p ose d 
t o t hera pe utic c o nce ntrati o ns of dr u gs k n o w n t o ca use Q T pr ol o n gat i on i n h u ma ns ( T o y os hi ma 
et al. 2 0 0 5). T h us, t he Q Tc c ha n ges t hat occ urre d i n t he males at 3 0/ 1 0 m g/ k g/ d ose BI D ma y be 
L O X O -3 0 5- r elate d; h o we ver, t hese were p h ysi o l ogi call y u ni m p orta nt a n d n o na d verse. 
P ote nti al effects of L O X O-3 0 5 o n t he ce ntral ner v o us s yste m ( C N S) were e val uate d as part o f 
t he G L P 2 8-da y re peat -d ose st u d y  in rat f u nct i onal o bser vat i onal batter y  ( F O B) tests a n d 
l oc o m o t or acti vity ( L M A) assess me nts. T here were n o L O X O - 3 0 5-relate d fi n di n gs i n t he F O B 
or L M A after 4 wee ks of d osi n g or at rec o ver y  at d oses of u p t o 5 0 0 m g/ k g/ dose BI D i n male 
rats a n d 1 7 5 m g/ k g/ d ose BI D i n fe male rats.
L O X O -3 0 5 ha d n o effect o n res pirat i on rate i n t he d o g at d oses u p t o 3 0/ 1 0 m g/ k g/ d ose BI D.
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
T o xic ol o g y
Tar gets of t o xicit y were c haracterize d i n re peate d d ose st u dies c o n d ucte d i n t w o rele va nt 
t o xicit y s pecies. Certai n tar gets (t he he mat o p oiet ic a n d l y m p h oi d s yste ms) were f o u n d i n b ot h 
t he rat a n d t he d o g. Rat s pecific c ha n ges i n t he pa ncreas are s pecies s pecific a n d see n wit h ot her 
B T K i n hi bit ors (B has kara n et al, 2 0 1 8 ). D o g s pecific c ha n ges i n l u n g a n d lar ge i ntest i ne were 
lesio ns c o ntri b ut i n g t o m ori b u n dity i n hi g h d ose a ni mals i n t he 2 8-d a y  st u d y. D oses e val uate d 
i n t he 2 8-d a y  d o g st u d y d e mo n strate d a stee p d ose res p o nse c ur ve f or t o xicit y a n d pr o n o u nce d 
c ha n ges i n he mat ol o gic para meters at hi g h e x p os ures. W he n c o m par i n g t he t w o s pecies at hi g h 
d oses a n d c orres p o n di n g e x p os ures, t he d o g was m ore s usce pti ble t o t he t o xic effects of L O X O -
3 0 5 t ha n t he rat a n d was c o nsi dere d t he m ore se nsiti ve s pecies.
1. 2. 3
Cli nic al E x perie nce
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1. 2. 4
Deter mi n ati o n of Rec o m me n de d P h ase 2 D ose
O n 5 Marc h 2 0 2 0, t he Safet y Re vie w C o m mittee Meet i n g f or St u d y L O X O-B T K - 1 8 0 0 1 
rec o m me n de d t hat 3 0 0 m g Q D be t he fi nal a n d hi g hest d ose e val uate d as part of t he d ose 
escalat i on. T hi s decisi on was base d o n se veral fact ors. Fi rst, d oses as lo w as 2 5 m g Q D s h o we d 
a nt i-t u mor acti vit y,  in cl u di n g a n u m ber of P Rs as earl y  as 8 wee ks at t his d ose. T he rel at i ons hi p 
bet wee n d ose a n d e x p os ure is li near fr o m 2 5 m g Q D t hr o u g h 3 0 0 m g Q D. T heref ore, t he d ose 
re gi me n of 2 0 0 m g Q D t o 3 0 0 m g Q D offers a n 
 
t ha n a p pears nee de d f or a nt i-t u mor acti vit y. S pecificall y , at a d ose of 2 0 0 mg Q D t he m ea n
 
At a d ose of 3 0 0 m g Q D, u n b o u n d mea n C mi n a n d C ma x of  u n b o u n d 
L O X O -3 0 5 l e vels are a p pr o xi matel y 
, res pecti vel y.
Fi nall y , d oses of 2 0 0 mg Q D t o 3 0 0 m g Q D a p pear t o be safe a n d well- t olerate d.
Gi ve n t he t otalit y of  efficac y, cli nical P K, a n d safet y data, t he sp o ns or a n d Safet y Re vie w 
C o m mittee deci de d t hat f urt her d ose escalat i on is n ot m e dicall y j ust ifie d a n d t heref ore n o 
ma xi m u m t olerate d d ose ( M T D) will be esta blis he d f or L O X O- 3 0 5.
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U p o n re vie w of t he safet y,  efficac y a n d P K data o btai ne d fr om pat ient s e nr olle d i n St u d y L O X O-
B T K -1 8 0 0 1, t he d ose of 2 0 0 m g Q D has bee n selecte d as t he rec o m me n de d d ose of L O X O-3 0 5 
f or c o nti n ue d cli nical e val uati on. 
T his rec o m me n dati o n was base d o n t he f oll owi n g: 

S af et y data were s u p p orti ve of t he 2 0 0 m g Q D d ose

M T D was n ot i de nt ifie d

S af et y data were als o s u p p ortive of  the 3 0 0 m g Q D d ose, wit h a li near d ose/e x p os ure 
r elat i ons hi p ( Cma x a n d A U C), pr o vi di n g a n e x p os ure mar g i n i n t he e ve nt t hat i ntri nsic or 
e xtri nsic fact ors lea d t o hi g her e x p os ures

C o m plete a n d parti al res p o nses were o bser ve d acr oss a ra n ge of d oses fr o m 2 5 m g Q D t o 
3 0 0 m g Q D

At  dose levels of  10 0 m g Q D a n d hi g her, t he tr o u g h u n b o u n d c o nce ntratio ns of  L OX O - 30 5 
i n plas ma e xcee de d t he I C9 0 f or B T K i n hi biti on t hr o u g h o ut t he d osi n g i nter val, w hic h is 
c o nsi dere d a rele va nt bi o mar ker base d o n t he n o n -c o vale nt i nteracti o n of L O X O-3 0 5 wit h 
B T K
1. 3
A ntici p ate d Ris ks
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1. 3. 1
A ntici p ate d Ris ks of L O X O -3 0 5 fr o m A ni m al St u dies
Base d o n t he m o st c o m m o n fi n di n gs i n t he a ni mal t o xic o l og y  st u dies, t he t he oretical ris ks of 
h u ma n e x p os ure t o L O X O -3 0 5 i ncl u de t he f o ll owi n g:

L oss of a p petit e

Decrease i n b o d y w ei g ht

Decrease i n w hi t e blo o d cell ( W B C ) i ncl u di n g ne utr o p hils (si g nifica nt), 
l y m p h oc ytes, m o n oc y tes, e osi n o p hils

Decreases i n re d cell mass ( re d blo o d cell  [R B C ], he m o gl obi n [ H b], he mat ocrit) a n d
r etic ulo c y t es

Decrease i n pl at el ets

Decrease i n al b u mi n, t otal pr otei n a n d/ or i ncrease i n gl o b uli n

I ncrease d b o d y t e mperat ure
C CI

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
Let har g y , decrease d e ner g y

L u n g a n d lar ge i ntesti ne i nfla m mat i on wi t h c orrelati ve la b orat or y fi n di n gs c o nsiste nt 
wi t h a n i nfla m mat or y res p o nse

Gastr oi ntesti nal ( GI) s y m pt o ms/si g ns: na usea, v o mit i n g, l o ose st o ols, diarr hea, 
a b d o mi nal disc o mf o rt, de h y drat i on

Effects o n a de vel o pi n g fet us (refer t o t he L O X O-3 0 5 I B)
T he oretical ris ks base d o n less c o m m o n or is olate d fi n di n gs i n t he a ni mal t o xic o l og y  st u dies 
i ncl u de:

I ncrease i n c h o lest er ol

Pr ol o n ge d cl otti n g ti mes

I ncreases i n li ver f u ncti on tests (e. g., Ala ni ne a mi n otra nsferase [A L T ])

I nfecti o ns

N o n -a d verse Q Tc i ncrease
C CI
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1. 3. 2
S afety E x perie nce Re p orte d wit h Ot her B T K I n hi bit ors
I br uti ni b (I) is a mar kete d B T K i n hi bit or i n C hi na a n d acala br uti ni b ( A) a n d za n u br uti ni b ( Z)
are mar kete d i n t he U nit e d S t at es wit h k n o w n safet y  pr ofiles. Of n ote, t he cli nical A E pr ofiles 
ass ociat e d wit h t hese irre versi ble B T K i n hi bit ors ma y be d ue t o b ot h o n tar get ( B T K) a n d off 
tar get (e. g., ot her T E C ki nases, e pid er m al gr o wt h fact or rece pt or [ E G F R ]) i n hi biti on, a n d 
L O X O -3 0 5 i s desi g ne d t o a v oi d t he off tar gets of c urre ntl y a vaila ble irre versi ble B T K 
i n hi bit ors. C o m m o nl y occ urri n g A Es o bser ve d i n patie nts recei vi n g treat me nt wit h t hese B T K
i n hi bit ors i ncl u de:

H e morr ha ge (I, A , Z)

Infecti o ns (I, A , Z)

C yt o pe ni as (I, A, Z), i ncl u di n g Gra de 3-4 ne utr o pe nia a n d t hr o m b oc yt o p e nia

C ar diac arr h yt hmias (I, A)

H y perte nsi o n (I, Z)

S ec o n d pri mar y mali g na ncies (I, A , Z)

T L S (I)

E m br y o -fetal t o xicit y (I, Z)

Ras h ( Z)

M usc ul os keletal pai n ( Z)

H y p o k al e mia ( Z)
1. 4
Be nefit/ Ris k
W he n vie we d as a w h o le, t he be nefit/ris k rati o f or L O X O-3 0 5 i n t his st u d y  is fa v ora ble. 
P ati e nts wit h B T K-de pe n de nt m ali g na ncies ( i. e., C L L/ S L L, M C L , W M , M Z L a n d ot her N H Ls) 
w h o ha ve faile d irre versi ble B T K i n hi bit ors d ue t o pr o gressi o n wit h or wit h o ut ac q uire d 
resista nce or t hose patie nts wit h treat me nt i nt olera nce t o prior B T K re prese nt p o p ulati ons wit h 
hi g h u n met nee d. As disc usse d i n Sect i on 1. 1 , a vaila ble t hera pies f or t hese patie nts pr o vi de 
s h ort-t er m palliati on (i . e., idelalisi b, c he m ot hera p y, a nti -C D 2 0 m o n o cl o n al  a nti b o d y t hera p y) or 
ha ve t he p ote ntial t o be ver y  t o xic (i.e., B C L 2 i n hi bit ors, C A R-T).
T heref ore, t here is a n ur ge nt 
nee d t o i de nt if y ne w tar gete d t hera pies t hat p ote ntl y  in hi bi t B T K ( wit ho ut or wi t h C 4 8 1 
s u bstitut i on m utati o ns i n t u m or cells) , w hile s pari n g ot her ki nase a n d n o n-ki nase off -tar gets t hat 
c o ntri b ute t o si g nifica nt t o xicit y.  T he earl y cli nical e x perie nce f or t his st u d y  s u g gests t hat 
L O X O -3 0 5 i s effecti ve i n patie nts wit h pre vi o us pr o gressi o n o n i br ut i ni b a n d b ot h wit h a n d 
wi t ho ut c o nfir me d C 4 8 1 m utati o n i n B T K.
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Because LOXO-305 is an experimental medicine, it is possible that unforeseen, unknown or 
unanticipated AEs and toxicities may occur. However, as detailed below, this clinical protocol 
is designed to mitigate risks to patients through a detailed plan for careful safety monitoring, 
systematic review of AEs, SAEs, and PK, and active pharmacovigilance review to assess for 
safety signals or trends. This phase 2 study of LOXO-305 is required to understand the anti-
tumor activity, safety and PK of LOXO-305 in patients with B-cell malignancies.

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2. STUDY OBJECTIVES AND ENDPOINTS
Table 2.1 shows the objectives and endpoints of the study.
Table 2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the anti-tumor activity of LOXO-305 
based on ORR according to Lugano Treatment 
Response Criteria for MCL and other NHL 
(Appendix A),International Workshop 
Guidelines for CLL/SLL (IWCLL 2018,
Appendix B) and WM (IWWM, Appendix C), 
or other criteria as appropriate to tumor type, as 
assessed by an IRC.

ORR by IRC
Secondary

To assess, for each cohort, the anti-tumor 
activity of LOXO-305.

ORR (by investigator)

BOR (by investigator and IRC)

DOR (by investigator and IRC)

PFS (by investigator and IRC)

OS

To determine the safety profile and tolerability 
of LOXO-305.

AEs, SAEs and TEAEs changes in hematology 
and blood chemistry values, assessments of 
physical examinations, vital signs, and ECGs

To characterize the PK properties of LOXO-
305.

Plasma concentration of LOXO-305 and PK 
parameters including, but not limited to, 
AUC0-24, Cmax, Tmax, T1/2

To determine the association of clinical 
response categories

Symptomatic response: improvement in cancer-
related symptoms among patients with MCL
associated with BOR

Functional response: improvement in physical 
function among patients with MCL associated 
with BOR

To collect PRO data to explore disease-related 
symptoms and HRQoL

Changes from baseline in disease-related 
symptoms and HRQoL measured by EORTC 
QLQ-C30

To determine the relationship between PK and 
drug effects, including efficacy and safety

Differences in efficacy and safety based on 
LOXO-305 PK parameters
Abbreviations: AE = adverse event; AUC0-24 = area under the concentration versus time curve from time 0 to 24 
hours; BOR = best overall response; Cmax = maximum drug concentration; CLL = chronic lymphocytic leukemia; 
DOR = duration of response; ECGs = electrocardiograms; EORTC QLQ-C30 = European Organisation for Research 
and Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0; HRQoL = health-related quality of life;
IRC = Independent Review Committee; MCL = mantle cell lymphoma; NHL = non-Hodgkin lymphoma; ORR = 
overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; PRO = patient 
reported outcomes; SAE = serious adverse event; SLL = small lymphocytic lymphoma; T1/2 = terminal elimination 
half-life; TEAE = treatment emergent adverse event; Tmax = time to maximum plasma concentration; WM = 
Waldenström macroglobulinemia.

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3. INVESTIGATIONAL PLAN
3.1
Study Design
This is an open-label, multi-center phase 2 study to evaluate efficacy and safety of oral LOXO-
305 as monotherapy in patients with MCL, CLL/SLL, and other types of B-cell NHL who have 
failed or are intolerant (as per the definitions in Appendix D) to standard of care.
LOXO-305 is administered in oral form at dose of 200 mg QD which will be fixed as total 
milligram (mg; as opposed to weight or body surface area [BSA]-based).
Approximately ~120 patients eligible for this trial will be enrolled to 1 of 3 cohorts (at least 30 
patients for Cohort 1, up to 30 patients for Cohort 2, and up to 50 patients for Cohort 3) assigned 
by tumor histology and prior treatment history. Cycle length will be 28 days.
Cohorts 1 through 3:

Cohort 1: Non-blastoid MCL patients with no CNS metastases and treated with prior
chemoimmunotherapy (refer to Table 3.1) and a BTK inhibitor (refer to Appendix E)
containing regimen

Cohort 2: CLL/SLL patients treated with a prior BTK inhibitor containing 
regimen

Cohort 3:
o
MCL or CLL/SLL patients not meeting the definitions of Cohort 1 or Cohort 2 and 
having failed or intolerant to standard of care, or unsuitable for standard of care in 
the opinion of investigator; 
o
Other B cell NHL (include but not limited to DLBCL, MZL and WM) patients 
having failed or intolerant to standard of care, or unsuitable for standard of care in 
the opinion of investigator. 
The Study Schema is provided in Figure 3.1.
This Phase 2 trial will consist of a Screening Period, a Treatment Period, an End of Treatment 
(EOT) visit, a Safety Follow-up (SFU) visit, and Long-term Follow-up (LTFU). Ongoing safety 
and disease assessments (for patients without PD), disease status, survival, and subsequent 
anticancer therapy(ies) will be assessed during LTFU.
A statistical justification for cohort size is discussed in Section 8.2.

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1 “Others” Cohort for:
a.
MCL or CLL/SLL patients not meeting the definitions of Cohort 1 or Cohort 2 and having failed or intolerant 
to standard of care, or unsuitable for standard of care in the opinion of investigator; 
b.
Other B cell NHL (include but not limited to DLBCL, MZL and WM) patients having failed or intolerant to 
standard of care or unsuitable for standard of care in the opinion of investigator.
Abbreviations: BTK = Bruton’s tyrosine kinase; BTKi = BTK inhibitor; CLL = chronic lymphocytic leukemia; 
DLBCL = diffuse large B cell lymphoma; MCL = mantle cell lymphoma; MZL = marginal zone lymphoma; NHL = 
non-Hodgkin lymphoma; PD = progressive disease; QD = once daily; SLL = small lymphocytic lymphoma; WM =
Waldenström macroglobulinemia
Figure 3.1
Study Schema
Table 3.1
Chemoimmunotherapy for MCL
Cohort
Therapy (including but not limited to)
Cohort 1: Non-blastoid MCL patients with 
no CNS metastases and treated with prior 
chemoimmunotherapy and BTK-inhibitor 
containing regimen
1.  high dose cytarabine based therapy: (e.g., R-CHOP/R-DHAP, 
R-hyperCVAD)
2. rituximab based therapy (e.g., R-CHOP, BR, VR-CAP)
Abbreviations:  BTK = Bruton’s tyrosine kinase; CNS = central nervous system; MCL = mantle cell lymphoma.
3.2
General Treatment Procedures
Patients will receive 200 mg LOXO-305 QD on Cycle 1 Day 1 (C1D1) and cycle length is 
28 days. Individual patients will continue LOXO-305 dosing until PD, unacceptable toxicity, or 
other reasons for treatment discontinuation, as outlined in Section 6.5. PD is defined by disease 
specific response criteria and assessed by the investigator. Patients with documented PD may be 
allowed to continue LOXO-305 if the patient is tolerating study drug and, in the opinion of the 
investigator, the patient is deriving clinical benefit from continuing LOXO-305, and 
continuation of treatment is approved by the sponsor until the patient gets the 2nd PD, 
unacceptable toxicity occurs, or the investigator agrees that the patient will no longer benefit 
from treatment. Patients continuing LOXO-305 treatment with sponsor approval should still 
follow on-treatment regular visit and relevant assessment.
All treated patients will undergo a SFU visit between 4 and 5 weeks after the last dose of study 

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treatment (i.e., 28 days after the last dose of study drug [+7 days]).
After treatment discontinuation, all patients will enter the LTFU period of the study. Patients 
who discontinue study treatment for reasons other than PD, withdrawal of consent, or initiation 
of a new anticancer therapy(ies), will also be assessed for progression of disease during LTFU 
until PD, withdrawal of consent, or initiation of a new anticancer therapy(ies). Once PD is 
confirmed (or 2nd PD is confirmed for patients continuing LOXO-305 treatment after 1st PD 
approval by sponsor), patients will be followed for survival status by telephone.

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4. SELECTION OF STUDY POPULATION
Potential patients must sign an informed consent form (ICF) before any study-specific screening 
tests may be conducted, except other specified in protocol.
4.1
Inclusion Criteria
1. Patients with histologically confirmed B-cell malignancy including:

Cohort 1 MCL:  Confirmed diagnosis of non-blastoid MCL with no CNS metastases and
with documentation of overexpression of cyclin D1 and/or t(11;14) and treated with prior 
chemoimmunotherapy and a BTK inhibitor-containing regimen;

Cohort 2 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 criteria treated 
with a prior BTK inhibitor containing regimen;

Cohort 3 Others:  Confirmed diagnosis of CLL/SLL by IWCLL 2018 criteria, WM with 
documentation of MYD88 mutation, MCL and other types of B-cell NHL (including but 
not limited to DLBCL and MZL) by World Health Organization (WHO) 2016 criteria, not 
otherwise specified in Cohorts 1 and 2, and having failed or intolerant to standard of care,
or unsuitable for standard of care in the opinion of investigator.
For patients in each Cohort:

All patients must have disease requiring treatment

Documented evidence of patients having failed or intolerant on the most recent line of 
therapy or relapse prior to study enrollment is required;

Patients in Cohort 1 and 2, relapsed/refractory or intolerant (as per the definitions in 
Appendix D) to a prior BTK inhibitor (investigational or approved, and either alone or in 
combination with other agents) treatment is required. 

Patients with MCL in Cohort 1who will be evaluated by Lugano criteria must have at least 
1 site of radiographically assessable disease (i.e., lymph node longest diameter (LDi)
>1.5 cm, extra nodal site >1.0 cm in LDi, or unequivocal hepatomegaly or splenomegaly
due to disease). Patients with non-measurable disease are eligible and will be assigned to
Cohort 3.

For CLL/SLL patients, at least 1 indication for treatment consistent with IWCLL 2018 
criteria (refer to Appendix F) is required.
2. Eastern Cooperative Oncology Group (ECOG) 0-2.
3. At least 18 years of age.
4. Confirmation of availability of tumor sample along with pathology report for central 
pathology review as described in Section 7.4 of the Protocol for patients enrolled in Cohort 
1.
5.
Adequate hematologic status, defined as the following on or within 7 days of C1D1 before 
treatment:
a.
Absolute neutrophil count (ANC) ≥0.75 ×109/L without granulocyte-colony stimulating 
factor (GCSF) supporting withing 7 days of Screening assessment; the patient may 
enroll below this threshold if there is documented bone marrow involvement 
considered to impair hematopoiesis.
b.
Platelet count ≥50 × 109/L not requiring transfusion or growth factors supporting within 
7 days of Screening assessment; the patient may enroll below this threshold if there is 

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d oc u m e nte d b o ne marr o w i n v o l ve me nt c o nsi dere d t o i m pair he mat o p oiesis.
c.
H b ≥8 g/ d L n ot re q uiri n g tra nsf usi o n or gr o wt h fact ors s u p p orti n g wit hi n 7 da ys of 
Scree ni n g assess me nt ; t he patie nt ma y e nr oll bel ow t his t hres h ol d if t here is 
d oc u m e nte d b o ne marr o w i n v o l ve me nt c o nsi dere d t o i m pair he mat o p oiesis.
d.
P ati e nts must be res p o nsi ve t o bl o o d or platelets tra nsf usi on s u p p ort if gi ve n f or b o ne 
marr o w i n v o l ve me nt i n d uce d c yt o pe nias.  Patie nts refract or y t o tra nsf usi on s u p p ort are 
n ot eli gi ble. See als o e xcl usi o n cri teria it e m 1 8.
6.
A de q uate c oa g ulat i on, defi ne d as act i vate d partial t hr o m b o plast i n ti me (a P T T) a n d 
pr ot hr o m bi n t i me ( P T) or (i nter nati o nal n or malize d rati o n [I N R]) n ot greater t ha n 1. 5 ×
u p per li mit of n or mal ( U L N ).
7.
A de q uate he pat ic f u ncti o n, defi ne d as:
a.
Ala ni ne a mi n otra nsferase (A L T ) or as partate a mi n otra nsferase ( A S T ) ≤2. 5 × U L N or 
≤5 × U L N wi t h d oc u me nte d li ver met astases
b.
T ot al  bilir u bi n ≤1. 5 × U L N or ≤3 × U L N wit h d oc u me nte d li ver metastases a n d/ or 
Gil bert’s Disease . If t otal bilir u bi n is > 1. 5 × U L N t he n direct/i n direct or 
c o nju gate d/ u nc o nj u gate d bili r u bi n tests s h o uld be perf or m e d for p ati e nts wit h 
he m o l ysis a n d/ or Gil bert’s s y n dr o me, t he y ma y be e nr olle d if u nc o nj u gate d/i n direct 
bilir u bi n is < 5 × U L N wi t h s p o ns or a p pr o val.
8.
A de q uate re nal f u nct i on defi ne d as creati ni ne cleara nce ≥3 0 m L/ mi n ute u si n g 
C oc kcr oft/ Ga ult F or m ula:
( 1 4 0 – a ge) × b o d y wei g ht ( k g) × 0. 8 5 (if fe male)
ser u m creati ni ne ( m g/ d L) × 7 2
9.
A bilit y t o s wallo w ta blets a n d c o m pl y wi t h o ut patie nt treat me nt, la b orat or y mo ni t ori n g, a n d 
re q uire d cli nic visits f or t he d urati o n of st u d y partici pat i on.
1 0. Willi n g ness of me n a n d w o me n of re pr o d ucti ve p ote ntial (defi ne d as f o ll owi n g me narc he 
a n d n ot p ost me n o pa usal [a n d 2 years of n o n -t hera p y-i n d uce d a me n orr hea] or s ur gicall y 
sterile) t o o bser ve c o n ve nti onal a n d hi g hl y  effect i ve birt h c o ntr ol met ho ds wi t h fail ure rates 
of  < 1 % f or t he d urati o n of treat me nt a n d f or 6 m o nt hs f oll owi n g t he l ast d ose of st u d y 
treat me nt; t his m ust i ncl u de barrier met h o ds s uc h as c o n d o m or dia p hra g m with s per mici dal 
g el . F or m ale s u bjects wit h a n o n- pre g na nt fe male par t ner of c hil d-beari n g p ote nti al a n d a 
w o m a n of c hil d -beari n g p ote nti al o n e of t he f oll owi n g hi g hl y effecti ve birt h c o ntr ol met h o ds 
wi t h a fail ure rate of less t ha n 1 % per year w he n use d c o nsiste nt l y a n d c orrectl y are 
rec o m me n de d:
a.
C o m bi ne d estr o ge n a n d pr o g esti n c o ntai ni n g h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti on o f o v ul at i on gi ve n orall y , i ntra va gi nall y, ortra ns der mall y
b.
Pr o gesti n -o nl y h or m o n al  c o ntrace ptio n ass oci ate d wit h in hi bit i on of o v ul at i on gi ve n 
orall y , b y inject i on, or b y i m pla nt
c.
I ntra uteri ne de vice (I U D)
d.
I ntra uteri ne h or m o ne-releasi n g s yste m (I U S)
e.
Bilateral t u bal o c cl usi o n
f.
Vasect o mize d part ner

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g. Sexual abstinence: considered a highly effective method only if defined as refraining 
from heterosexual intercourse during an entire period of risk associated with the study 
treatment. The reliability of sexual abstinence will be evaluated in relation to the 
duration of the study and to the usual lifestyle of the patient (CTFG 2014).
Birth control methods unacceptable for this clinical trial are:
a.
Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
b. Withdrawal (coitus interruptus)
c.
Spermicide only
d. Lactational amenorrhea method
Sperm donation is prohibited during the duration of participation on this protocol and for 6 
months after the last dose of study drug.
4.2
Exclusion Criteria 
11. Investigational agent or anticancer therapy (including some Chinese traditional medicine 
with anti-tumor indication in label) within 5 half-lives or 14 days, whichever is shorter, prior 
to planned start of LOXO-305 except therapeutic monoclonal antibody treatment must be 
discontinued a minimum of 4 weeks prior to the first dose of LOXO-305. In addition, no 
concurrent systemic anticancer therapy is permitted.
a.
Continuation of certain standard of care anticancer therapies, including hormonal therapy 
for localized breast and prostate cancer, is allowed, provided they are not on the list of 
prohibited concomitant medications. Refer to Section 6.3.2 for allowed and
Section 6.3.3 for prohibited medications.
12. Major surgery (excluding placement of vascular access or biopsy) within 4 weeks prior to 
planned start of LOXO-305.
13. Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of 
study treatment, except for patients receiving radiation to pelvis, skull or sternum (bone 
marrow area)or receiving whole brain radiotherapy, which must be completed at least 4 
weeks prior to the first dose of study treatment.
14. Patients requiring therapeutic anticoagulation with warfarin.
15. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for 
Adverse Events (CTCAE [version 5.0]) Grade 2 at the time of starting study treatment 
except for alopecia or otherwise specified in this eligibility criteria.
16. History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-
modified T-cell (CAR-T) therapy within the 60 days prior to planned start of LOXO-305
treatment or with any of the following:
a.
Active graft versus host disease (GVHD)
b. Cytopenia requiring transfusion support reflecting incomplete blood count recovery post-
transplant
c.
Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of 
neurotoxicity > Grade 1 from CAR-T therapy
d. Ongoing immunosuppressive therapy
17. Known CNS involvement by systemic lymphoma. Patients with previous treatment for CNS 

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involvement who are neurologically stable (neurological symptoms and CNS imaging are 
stable and steroid dose is stable for 14 days prior to the first dose and no CNS surgery or 
radiation has been performed for 28 days, 14 days if stereotactic radiosurgery [SRS]) and 
without evidence of disease may be eligible and enrolled to Cohort 3 if a compelling clinical 
rationale is provided by the investigator and with documented sponsor approval.  Primary 
CNS lymphoma is excluded.
18. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], 
idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced, or concomitant 
therapy escalated within the 4 weeks prior to study enrollment is required to maintain 
adequate blood counts.
19. Significant cardiovascular disease defined as:
a.
Unstable angina, or
b. History of myocardial infarction within 6 months prior to planned start of LOXO-305, or
c.
Documented left ventricular ejection fraction (LVEF) by any method of ≤45% in the 
12 months prior to planned start of LOXO-305, assessment of LVEF during screening 
should be performed in selected patients as medically indicated, or
d. Any Class 3 or 4 cardiac disease as defined by the New York Heart Association 
Functional Classification (refer to Appendix G), or
e.
Uncontrolled or symptomatic arrhythmias
20. Prolongation of the QT interval corrected of heart rate (QTcF) >470 msec on at least 2/3 
consecutive ECGs, and mean QTcF >470 msec on all 3 ECGs, during Screening. QTcF is 
calculated using Fridericia’s Formula (QTcF): QTcF = QT/(RR0.33).
a. Correction of suspected drug-induced QTcF prolongation can be attempted at the 
investigator’s discretion and only if clinically safe to do so with either discontinuation of 
the offending drug or switch to another drug not known to be associated with QTcF
prolongation (agents known to cause QTc prolongation refer to Appendix H).
21. Patients who experienced a major bleeding event or grade ≥3 arrhythmia on prior treatment 
with a BTK inhibitor.
NOTE: Major bleeding is defined as bleeding having one or more of the following features:  
potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; 
bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or 
bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, 
or intracranial bleeding or intramuscular bleeding with compartment syndrome).
22. Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except for fungal 
nail infection), or other clinically significant active disease process which inthe opinion of 
the investigator and the sponsor makes it undesirable for the patient to participate in the trial.
Screening for chronic conditions is not required.
23. Patients who have tested positive for human immunodeficiency virus (HIV) are excluded
due to potential drug-drug interactions between anti-retroviral medications and LOXO-305 
and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For 
patients with unknown HIV status, HIV testing will be performed at Screening and result 
should be negative for enrollment.
24. Have active hepatitis B or C.
a.
Patients with detectable hepatitis B virus (HBV) DNA and controlled disease may be 

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permitted on therapy with sponsor approval. Concurrent viral suppressive treatment will 
be required for patients with detectable HBV DNA. Refer to Section 6.3.2 for allowed 
and Section 6.3.3 for prohibited medications.
b.
Patients with history of hepatitis C virus (HCV) infection who have completed viral 
suppressive therapy and have a viral load below the limit of quantification are allowed.
25. Clinically significant active malabsorption syndrome or other conditions likely to affect GI 
absorption of the study drug.
26. Current treatment with certain strong CYP3A4 inhibitors or inducers (refer to Appendix I) 
and/or strong P-gp inhibitors within 7 days before starting LOXO-305 (refer to Appendix J)
27. Pregnancy or lactation.
28. Active second malignancy unless in remission with life expectancy >2 years and with 
documented sponsor approval. Examples include:
a.
Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without 
current evidence of disease
b. Adequately treated cervical carcinoma in situ without current evidence of disease
c.
Localized (e.g., lymph node negative) breast cancer treated with curative intent with no 
evidence of active disease present for more than 3 years and receiving adjuvant 
hormonal therapy
d. Localized prostate cancer undergoing active surveillance
29. Prior treatment with LOXO-305.
30. Patients with known hypersensitivity to any component or excipient ofLOXO-305.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
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L Y 3 5 2 7 7 2 7
5.
E N R O L L M E N T P R O C E D U R E S
F or all patie nts, a c o p y  of t he re dacte d M olec ular Pat h ol o g y Re p ort m ust be s u b mit te d t o t he 
sp o ns or or desi g nee d uri n g scree ni n g f or re vie w pri or t o patie nt e nr ol l me nt. T he pla n ne d c o h ort
of  t he st u d y a n d a patie nt n u m ber will be assi g ne d t hat will be use d t hr o u g h o ut b ot h Scree ni n g 
a n d st u d y p artici pat i on.
P ati e nts w h o ca n n ot c o m plete t he pr oce d ures wit hi n t he scree ni n g wi n d o w ma y be rescree ne d , 
a n d certai n scree ni n g pr oce d ures ma y n ot nee d t o be re peate d wit h d oc u m e nte d sp o ns or 
a p pr o val. C ertai n pr oce d ures t hat were o btai ne d as part of t he patie nt’s sta n dar d care pri or t o 
pr o vi di n g i nf or me d c o nse nt f or t his st u d y (i.e. , he mat ol o g y, i ma gi n g) , ma y be utilize d f or 
scree ni n g or baseli ne p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol-s pecifie d criteria,  a n d 
were perf or me d wit hi n t he ti me fra me defi ne d i n t he Ta ble 7. 1 .
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y b e 
rescree ne d, o nl y aft er disc ussio n wi t h a n d per missi o n fr o m t he Lill y cli nical researc h p h ysicia n 
(C R P ) or desi g nee. P ati e nts ma y be eli gi ble f or re-scree ni n g u p t o 2 ti mes i n a n y o f t he 
f oll owi n g circ u msta nces:

P ati e nts w h o ha ve bec o me eli gi ble t o e nr oll i n t he st u d y as t he res ult of a pr ot oc ol
a me n d me nt.

P ati e nts w h ose stat us has c ha n ge d s uc h t hat t he eli gi bilit y crit erio n t hat ca use d t he patie nt t o 
scree n fail w o ul d n o l o n ger ca use t he patient  t o scree n fail a gai n.

P ati e nts w h o c o mplete scree ni n g a n d meet all i ncl usi o n a n d e xcl usi o n re q uire me nts b ut are 
u na ble t o be e nr o lle d d ue t o e xte n uati n g circ u msta nces (s uc h as se vere weat her, or c hil d 
ill ness).
Eac h ti me rescree ni n g is perf or me d , t he i n di vi d ual m ust si g n a ne w I C F a n d will be assi g ne d a 
ne w i de nt ificati o n n u m ber.
T his is a n o pe n -la bel st u d y a n d all patie nts w h o meet all criteria f or e nr oll me nt will recei ve 
L O X O -3 0 5 treat m e nt. Dis pe nsi n g a n d trac ki n g L O X O -3 0 5 treat me nt will be acc o m p lis he d 
usi n g a n i nteracti ve We b/ v o ice res p o nse s yste m (I x R S).

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6. TREATMENTS AND ADMINISTRATION
6.1
Investigational Product
LOXO-305 will be provided by the sponsor as tablets. To reduce variability in oral absorption, 
a spray-dried dispersion (SDD) tablet formulation was developed for use in humans (refer to 
Section 1.2.2-Pharmacokinetics). The tablet will be provided to the sites for distribution to the 
patient for outpatient administration at the assigned dose level.
The site pharmacist will dispense bottles to the patient in an amount necessary to allow for 
outpatient administration at the assigned dose level. Dosing is intended to be fixed (i.e., not 
weight-based or BSA-based).
Tablets are to be stored at room temperature according to investigational product label.
6.2
LOXO-305 Administration
6.2.1
General Dosing Instructions
All patients taking LOXO-305 should not consume grapefruit or grapefruit products, starfruit, 
Seville oranges or marmalade containing Seville oranges from the 3 days prior to start of study 
therapy until therapy is stopped. Prohibited concomitant medications and contraindications are 
discussed in Sections 6.3.3 and 6.3.4, respectively.
LOXO-305 will be administered to patients in oral tablet form at 200 mg QD, and cycle length 
will be 28 days. Dosing for an individual is recommended at a consistent time each day.
LOXO-305 may be taken with or without food and drink.
The patient will keep a daily diary to record dosing compliance of oral study treatment, which 
will also be assessed at each clinic visit by means of a tablet count in the returned bottle(s). Late 
doses (i.e., 4 or more hours after scheduled time) should be noted in the diary. Doses that are 
late by more than 6 hours should not be made up and recorded in the dosing diary as missed. 
Vomiting after dosing should be noted in the diary and a vomited dose should not be re-dosed or 
replaced. 
Patients will begin to receive LOXO-305 on C1D1 and continue study treatment dosing in a 
continuous 28-days cycle until PD, unacceptable toxicity, or other reason for treatment 
discontinuation. Patients with documented PD may be allowed to continue study treatment if 
the patient is tolerating study drug and, in the opinion of the investigator, the patient is deriving 
clinical benefit from continuing study treatment (including but not limited to no rapid disease 
progression, stable performance status, and no serious complications due to disease progression)
and continuation of treatment is approved by the sponsor until the patient gets the 2nd PD, 
unacceptable toxicity occurs or the investigator agrees that the patient will no longer benefit 
from treatment. Patients must provide written informed consent prior to receiving additional 
LOXO-305 treatment, using an ICF describing any reasonably foreseeable risks or discomforts, 
or other alternative treatment options. Patients continuing LOXO-305 treatment with sponsor 
approval should still follow on-treatment regular visit and relevant assessment, and are 
recommended with close tumor assessment (i.e., 4-8 weeks after 1st PD) to evaluate patients’ 

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 4 5
L Y 3 5 2 7 7 2 7
be nefit fr o m t he f o ll owi n g treat m e nt per i n vesti gat or discreti o n .
Effects of L O X O -3 0 5 o n c oa g ul at i on are u n k n o w n. T h us , pati e nts u n der g oi n g maj or s ur gical 
pr oce d ures s h o ul d ha ve L O X O -3 0 5 hel d at l east 3 da ys pri or a n d 3 da ys p ost pr oce d ure a n d f or 
s ur ger y o n C N S or li ver or ot her critical or ga ns w hic h ma y be m o st pr o ne t o blee d, L O X O - 3 0 5 
s h o uld be hel d at l east 7 da ys pri or a n d 7 da ys p ost pr oce d ure ; t he sp o ns or s h o ul d be n otifie d of 
t he pla n ne d pr oce d ure a n d pla n ne d d ose h ol d.
6. 2. 2
D ose Del ays/ M o dific ati o ns
C ycles are 2 8 da y s i n d urati on re gar dless of d ose i nterr u pti o n u nless t he d ose i nterr u pti o n 
i ncl u des Da y 1 of t he ne xt c ycle i n w hic h case t he ne xt c ycle will start wit h res u m pt i on of st u d y  
dr u g. I n t his sit uati o n, disease assess me nts s h o ul d c o nti n ue t o f oll ow t he ori gi nal sc he d ule.
D ose h ol d or re d ucti o n will be i m ple me nte d f or a n y patie nt w h o e x perie nces a cli nicall y 
sig nifica nt A E c o nsi dere d relate d t o L O X O -3 0 5 as assesse d b y C T C A E v 5. 0 .  F or C L L/ S L L 
pati e nts, he mat ol o gic t o xicit y will als o be assesse d b y  C T C A E v 5. 0. 
T o xicit ies s uc h as na usea, v omit i ng, or di arr hea, or dizzi ness or de h y drati o n relate d t o t hese 
s y m pt o ms, ma y be ma na ge d wit h i ncrease d s u p p orti ve care, i ncl u di n g h y drati on, el ectr ol yt e 
r e plet i on, a n d t he use of a nt i-e met ics s uc h as ser ot o ni n t ype 3 ( 5 -H T 3) a nta g o nists a n d/ or a nti -
di arr heal me dicat i ons s uc h as l o pera mi de as a p pr o priate.
F or a patie nt w h o e x perie nces a cli nicall y si g nifica nt A E c o nsi dere d relate d t o L O X O - 3 0 5 (e. g., 
≥Gra de 3 A E , Gra de 2 A E n ot res ol ve d wit hi n 4 8 h o urs wit h a p pr o priate s u p p orti ve care [e. g., 
na usea n ot i m pr o ved wi t h a ntie metics] as assesse d b y C T C A E v 5. 0 a n d c o nsi dere d i nt olera ble 
b y t he patie nt or t he i n vest i gat or, or A E m o re t ha n 1 gra de c ha n ge fr o m baseli ne if baseli ne is 
Gra de 2 or a b o ve) , i n vesti gat or s h o ul d disc uss wit h s p o ns or a n d m a y ha ve L O X O -3 0 5 d osi n g 
hel d f or u p t o 2 8 da y s t o e valuate t he A E a n d t o all o w f or rec o ver y  (t o Gra de 1 or less or 
baseli ne if baseli ne is Gra de 2 or a b o ve).
U p o n rec o ver y , i n vesti gat or s h o ul d disc uss with s p o ns or a n d t he patie nt ma y restart t hera p y as 
o ut li ne d i n (Ta ble 6. 1 ) if it is c o nsi dere d i n his/ her best i nterest t o c o nti n ue t hera p y. A n y 
c o nti n ued d osi n g bef ore a cli nicall y si g nifica nt A E rec o ver s t o Gra de 1 or less, or baseli ne if 
baseli ne is Gra de 2 or a b o ve , s h o uld be disc usse d a n d get d oc u me nte d sp o ns or a p pr o val. If t he 
A E d oes n ot rec o ver t o Gra de 1 or less, or baseli ne if baseli ne is Gra de 2 wit hi n 2 8 da ys , t he 
pati e nt will ha ve treat me nt per ma ne nt l y disc o nti n ue d, u nless t here is a c om pelli n g cli nical 
r atio nale f or d ose h ol di n g f or m ore t ha n 2 8 d a y s or a ddi tio n al  d ose re d uctio n(s) arti c ulate d b y 
t he in vest i gat or a n d a p pr o ve d b y t he sp o ns or. F or eac h patie nt , a ma xi m u m of 2 d ose re d ucti o ns 
will be all o we d, u nless t here is a c o m pelli n g cli nical rati o nale f or a d dit i onal d ose re d ucti o n(s) 
artic ulate d b y t he in vest i gat or a n d a p pr o ve d b y t he sp o ns or ( Ta ble 6. 1 ).

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Table 6.1
Suggested Dose Reduction Levels for LOXO-305 for Toxicity Management
Adverse Events*
Occurrences 
Requiring Dose 
Modification
LOXO-305 
(Starting dose 
200 mg QD)
LOXO-305
Modification
•
≥Grade 3 AE
•
Grade 2 AE not resolved 
within 48 hours with 
appropriate supportive care
and considered intolerable 
by the patient or the 
investigator
•
AE more than 1 grade 
change from baseline if 
baseline is Grade 2 or above
First occurrence
No change
Hold LOXO-305 until recovery to 
Grade 1 or baseline; may restart at 
original dose level (200 mg QD)
Second occurrence
100 mg QD
Hold LOXO-305 until recovery to 
Grade 1 or baseline; may restart at 
one dose level lower (100 mg QD)
Third occurrence
50 mg QD
Hold LOXO-305 until recovery to 
Grade 1 or baseline; may restart at 
one dose level lower (50 mg QD)
Fourth occurrence
Discontinue
Discontinue
*
For patients enrolled with AST or ALT >1.5 × ULN at baseline a dose interruption should be implemented if 
the AST or ALT >3 × baseline or AST or ALT ≥2 × baseline with concurrent total bilirubin ≥2 × ULN.  An 
evaluation for potential alternative causes of liver dysfunction should be conducted.  Dose interruptions and/or 
modifications may also be undertaken for Grade 2 AEs deemed to be intolerable in the setting of chronic study 
drug administrations.  Patients found to have treatment-emergent laboratory toxicity of Grades 3 or 4 will be 
monitored at least weekly until resolution.
Patients who have been dose-reduced and who tolerate LOXO-305 without toxicity for at least 
2 weeks may be re-escalated to the next higher dose level, not to exceed 200 mg QD, at the 
discretion of the investigator and approved by the sponsor. If the LOXO-305 dose is reduced for 
apparent treatment-related toxicity, the dose need not be re-escalated.
All dose interruptions and dose modifications and the reasons for those changes will be recorded 
in the Case Report Form (CRF).
6.3
Prior and Concomitant Medications
6.3.1
General
Concomitant medications will include ongoing medications and all medications that were 
administered within 14 days prior to the planned start of study drug or from Screening
(whichever is shorter) through the SFU visit (at least 28 days [+7 days] after the last dose of 
study drug) and are to be recorded in the CRF. These are to include prescription and 
nonprescription medications, transfusions, vitamins, nutritional supplements, and other 
remedies. Excluded medications are indicated in the Exclusion Criteria (Section 4.2).
6.3.2
Allowed Concomitant Medications
Standard supportive medications may be used in accordance with institutional guidelines and 
investigator discretion. These may include hematopoietic growth factors to treat neutropenia, 
anemia, or thrombocytopenia in accordance with American Society for Clinical Oncology 
guidelines; red blood cell (RBC) and platelet transfusions; anti-emetic, analgesic, and 
antidiarrheal medications; electrolyte repletion (e.g., calcium and magnesium) to correct low 
electrolyte levels; glucocorticoids (approximately 20 mg per day prednisone or equivalent for
~14 days, unless there is a compelling clinical rationale for a higher dose articulated by the 

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investigator and approved by the sponsor), including short courses to treat asthma, chronic 
obstructive pulmonary disease, etc.; thyroid replacement therapy for hypothyroidism; and 
bisphosphonates, denosumab. and other medications for the treatment of osteoporosis, 
prevention of skeletal-related events from bone metastases, and/or hypoparathyroidism.  
Continuation of standard of care medications, including hormonal therapy for patients with 
prostate cancer (e.g., gonadotropin-releasing hormone [GnRH] or luteinizing hormone-
releasing hormone [LHRH] agonists) and breast cancer (e.g., GnRH/LHRH agonists, aromatase 
inhibitors, selective estrogen receptor modulators [SERMs] or degraders [SERDs]), that the 
patient has been on for the previous 28 days, are allowed, provided they are not on the list of 
prohibited concomitant medications (refer to Section 6.3.3).
Local treatment while receiving LOXO-305 (e.g., palliative radiation therapy or surgery for 
bone metastases) is permitted with documented sponsor approval. If the lesion that is to be 
treated is a target lesion, the lesion will be censored at the time of treatment. However, the patient 
may remain on study provided there are other target lesions that can be followed for response 
assessment. However, the sponsor recommends holding LOXO-305 for ~3-5 half-lives before 
and after radiation therapy or surgery. Any concern for disease flare due to a prolonged LOXO-
305 dose interruption should be discussed with the sponsor, who may permit holding LOXO-
305 for a shorter period of time.
6.3.3
Prohibited Concomitant Medications
As LOXO-305 is a substrate of CYP3A4, patients should not take strong inhibitors or inducers 
of CYP3A4 as they could alter drug’s PK. This restriction includes herbal products, such as 
St John’s wort, which may decrease the drug levels of LOXO-305. Moderate inhibitors or 
inducers of CYP3A4 should be taken with caution. Refer to Appendix I. Grapefruit, Seville 
oranges, starfruit or products with these fruits should be avoided for the duration of treatment.
Given that LOXO-305 is a substrate of P-gp, patients should not take strong inhibitors of P-gp 
as they could alter drug’s PK. Mild inhibitors of P-gp should be taken with caution; refer to 
Appendix J.
If during the study, patients require initiation of treatment with strong inhibitors or inducers of 
CYP3A4 or P-gp inhibitors, for clinical reasons, then the sponsor should be consulted to 
determine whether LOXO-305 should be stopped, and therefore whether the patient should be 
removed from the study. Moderate inhibitors or inducers of CYP3A4 should be taken with 
caution. Any exceptions to the above must be approved by the sponsor.
In addition, except as indicated in Section 6.3.2, patients are not allowed to receive concomitant 
systemic anti-cancer agents (including some Chinese traditional medicine with anti-tumor 
indication in label), hematopoietic growth factors for prophylaxis in Cycle 1, therapeutic 
monoclonal antibodies, drugs with immunosuppressant properties, or any other investigational 
agents besides LOXO-305. No new or alternative systemic anticancer therapy is allowed prior 
to documentation of PD in accordance with protocol-specified disease response criteria.
6.3.4
Contraindications
LOXO-305 is contraindicated in patients with known hypersensitivity to any of its tablet 
components.

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6. 4
D ur ati o n of Tre at me nt
It is a ntici pate d t hat a patie nt o n t his st u d y will recei ve treat me nt wit h o pe n-label L O X O - 3 0 5 
u nt il t he patient  is a ble t o o btai n c om merciall y a vaila ble L O X O -3 0 5 i n C hi na , t he patie nt d oes 
n ot m e et criteria re q uirin g disc o nt i n uati on of treat me nt (refer t o Secti o n 6. 5 ), a n d t he patie nt’s 
parti ci pat i on i n t he st u d y has n ot e n de d. U p o n c o m mercial a vaila bilit y i n C hi na t here ma y be 
a d ditio nal  o ptio ns f or t he patie nt t o c o nti n ue t o recei ve L O X O-3 0 5 o nce t he re g ulat or y  
re q uire me nts are satisfie d. T hese ma y i ncl u de b ut are n ot li mit e d t o a r oll o ver trial, patie nt 
assista nce (s h o ul d t he patie nt q ualif y), or c o m mercial L O X O-3 0 5. T he st u d y  ma y be ter mi nate d 
if L O X O -3 0 5 d oes n ot o b tai n mar keti n g a p pr o val or t he de vel o p me nt of L O X O-3 0 5 is n o 
l on ger bei n g p urs ue d b y  t he sp o ns or. T he s p o ns or als o reser ves t he ri g ht t o disc o nti n ue t he 
st u d y for cli nical  or a d mi nistrati ve reas o ns at a n yti me.
6. 5
Disc o nti n u ati o n of St u d y I nter ve nti o n
P ati e nts will be a d vise d t hat t he y ar e free t o disc o nti n ue st u d y treat me nt at a n y time a n d t hat 
t he y will be f oll owe d f or s ur vi val after disc o nti n ui n g treat me nt (refer t o Secti o n 7. 1 7 ). O ver t he 
c o urse of t he st u d y, t he in vest i gat or a n d/ or t he sp o ns or s h o ul d re m o ve a patie nt fr o m treat me nt 
f or a n y of t he reas o ns liste d bel o w:

P D
E xce pti o n: Patie nts wit h d oc u me nte d P D w h o a re t olerat i n g st u d y t hera p y a n d, i n t he 
o pi ni o n of t he in vest i gat or, are deri vi n g cli nical be nefit fr o m c o nti n ui n g st u d y treat me nt, 
ma y c o nt i n ue treat me nt wit h d oc u me nte d sp o ns or a p pr o val u nt il t he patie nt gets t he 2 n d
P D, u nacce pta ble t o xicit y occ urs or t he i n vest i gat or a grees t hat t he patie nt will n o l o n ger 
be nefit fr o m treat me nt. Patie nts c o nti n ui n g L O X O -3 0 5 treat me nt wit h wri tte n i nf or me d 
c o nse nt a n d s p o ns or a p pr o val s h o ul d still f oll ow o n -treat me nt re g ular visit a n d rele va nt 
assess me nt , a n d are rec o m me n d wi t h close t u mor assess me nt (i.e., 4- 8 wee ks after 1 st
P D ) t o e val uate patie nts’ be nefit fr om t he f oll owi n g treat m e nt per i n vesti gat or discret i on .

U nacce pta ble t o xicit y

I nterc urre nt ill ness c om pr o misi n g a bilit y t o fulfill pr ot oc ol re q uire me nts

Pre g na nc y

Re q ui re me nt f or alter nati ve treat me nt i n t he o pi ni o n of t he in vest i gat or, u nless s uc h 
treat me nt is te mp or ar y  (e. g., lo c al  r a diat i on or s ur ger y  for di sease t hat d oes n ot meet t he 
defi nit i on o f P D)

D ose dela y  > 2 8 da ys, u nless a cli nical nee d f or prol o n ge d dela y  has bee n deter mi ne d b y 
t he in vest i gat or wit h d oc u me nte d sp o ns or a p pr o val

Si g nifica nt n o nc o m p lia nce with pr ot oc ol (Pati e nts ta ke < 7 5 % or ≥1 2 5 % of t he pla n ne d 
d oes as prescri be d per c ycle)

Wit h dra wal o f c o nse nt b y t he patient

L os t to f oll o w - u p

Deat h

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
Study terminated by sponsor
At the time a patient discontinues treatment, all safety data normally required at the EOT and 
SFU visit will be obtained if possible, as outlined in Section 7.15. Patients will enter LTFU 
where they may be required to undergo disease assessments (refer to Section 7.17).
6.5.1
Discontinuation of Inadvertently Enrolled Patients
If the sponsor or the investigator identifies a patient who did not meet enrollment criteria and 
was inadvertently enrolled, a discussion must occur between the Lilly CRP and the investigator 
to determine if the patient may continue in the study. If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CRP to allow the 
inadvertently enrolled patient to continue in the study with or without study drug.  Patients who 
are discontinued from study drug will have follow-up procedures performed as shown in the 
Table 7.1.
6.6
Discontinuation from Study
Discontinuation from the study and reasons for end of study could be:

Withdrawal of consent by the patient

Lost to follow-up

Death

Study terminated by sponsor

The clinical trial will be discontinued or terminated in case of an unacceptable risk, any 
relevant toxicity, or a negative change in the risk/benefit assessment.  These might 
include the occurrence of adverse events which in character, severity or frequency are 
new in comparison to the existing risk profile.  In addition, any data deriving from other 
clinical trials or toxicological studies which negatively influence the risk/benefit 
assessment might cause discontinuation or termination of the study.
For each disease-defined cohort, consideration of termination will use the same safety 
considerations.  Individual cohorts may be terminated based on inadequate enrolment, low ORR, 
or shorter than anticipated duration of response (DOR).  An individual cohort close but overall 
enrolment to the study may continue.
Sample size justification for each cohort is provided in Section 8.2.
Patients who are discontinued from the study will have follow-up procedures performed as 
shown in the Table 7.1.
6.7
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Study site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or who the site is 
otherwise unable to follow-up.

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Study site personnel, or an independent third party, will attempt to collect the survival status for 
all enrolled patients who are lost to follow-up, including enrolled patients who do not receive 
study drug, within legal and ethical boundaries. Public sources may be searched for survival 
status information.  If the patient’s survival status is determined, the survival status will be 
documented, and the patient will not be considered lost to follow-up.
Lilly personnel will not be involved in any attempts to collect survival status information.

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7. STUDY PROCEDURES AND ASSESSMENTS
Descriptions of assessments are provided in Sections 7.1 through 7.17 below. Specific timing 
requirements for study procedures and assessments by diagnosis at enrollment are provided in 
Table 7.1.
For PK sampling days and time points, see Table 7.2.
Routine laboratories, for example serum chemistries, hematology, and urinalysis, will be
performed locally. Unless otherwise noted, the routine laboratories and procedures will be 
performed prior to dosing as noted, and routine evaluations performed within 2 days prior of the 
visit day will not be considered protocol deviations.
Additional guidance for study assessments and procedures and collection of samples for central 
assessments is provided in Appendix K and the Laboratory Manual.

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Table 7.1
Schedule of Assessments
Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(± 2
Days)
D15
(± 2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±3 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
Results of tests below are required for enrollment
Informed consent
X
Medical, surgical, 
malignancy 
historya
X
Physical 
examination and 
ECOGb
X
X
X
X
Day 1 each cycle
X
X
Vital signsc
X
X
X
X
Day 1 each cycle
X
X
12-lead ECGd
X
X
X
Day 1 every other cycle, 
C2 through 12, then as 
clinically indicated
X
X
Hematologye
X
X
X
X
Day 1 each cycle
X
X
Blood chemistriesf
X
X
X
X
Day 1 each cycle
X
X
Coagulation panelg
X
As clinically indicated
Urinalysish
X
X
Day 1 each cycle through 
C12, then as clinically 
indicated
X
Serum or urine 
pregnancy test (if 
applicable)i
X
Day 1 each cycle
HIVj
X

J2N-MC-JZNJ (b) Clinical Protocol
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Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(± 2
Days)
D15
(± 2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±3 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
CMV, Hepatitis B 
and Hepatitis C 
testingj
X
Documentation of 
histologic diagnosis 
and relevant
biomarkersk
X
Documentation or sampling required during screening but results not required prior to enrollment
Tumor sample 
obtained for central 
pathology reviewl
X
Bone marrow 
aspirate and/or
biopsym
X
For confirmation of CR and at PD (optional) (refer to Appendix K)
Upper and lower 
endoscopyw
X
For confirmation of CR in MCL patients of Cohort 1 only (refer to Appendix K)
For CLL/SLL
Lymphocyte 
subsetsn
X
Every 8 
weeks 
beginning 
with C3D1 
(±7 days)
Every 12 weeks 
(±2 weeks) 
beginning with 
C13D1 for 1 
year, then every 
6 cycles (±4 
weeks) after
X
Xx

J2N-MC-JZNJ (b) Clinical Protocol
Page 54
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Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(± 2
Days)
D15
(± 2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±3 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
For patients 
with known 
paraprotein: 
SPEP, serum 
immunofixation, 
serum FLC, 
quantitative
Immunoglobulins, 
total proteino
X
Every 8 
weeks 
beginning 
with C3D1 
(±7 days)
Every 12 weeks 
(±2 weeks) 
beginning with 
C13D1 for 1 
year, then every 
6 cycles (±4 
weeks) after
X
X x
Radiologic 
disease 
assessmentp
X
Every 8 
weeks 
beginning 
with C3D1
(±7 days)
Every 12 
weeks
(±2 weeks) 
beginning 
with C13D1
for 1 year, 
then every 6 
cycles
(±4 week
s) after
X
X x
Items starting with Cycle 1
Blood samples 
for PKq
Refer to Table 7.2
Telephone 
follow-up
X
X
Survival statusr
X
LOXO-305 
administration
X
X

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 5 5
L Y 3 5 2 7 7 2 7
E v al u ati o n
Scree ni n g *
C ycle 1
( D 1-D 2 8)
C ycles 2 
t hr o u g h 
1 2
C ycles 1 3 
a n d Hi g her
E O T * *
S F U
L T F U
8 0 1 
8 0 2 - 8 X X
Visit Wi n d o w
D 0
(- 2 8 D a ys )
D 1
(- 2
D a ys)
D 8
( ± 2
D a ys)
D 1 5
( ± 2
D a ys)
D 2 2
( ±2
D a ys)
D 1
( ± 3
D a ys)
D 1
( ±3 D a ys)
≤7 d a ys 
after l ast d ose 
or decisi o n t o 
ter mi n ate 
tre at me nt
2 8 d a ys ( + 7 
d a ys) after l ast 
d ose of st u d y 
dr u g
E ver y 3 m o nt hs
± 1 m o nt h f or 
u p t o 2 ye ars 
after l ast d ose 
of st u d y dr u g
Patie nt d osi n g 
diar y s
X
X
C o nc o mita nt 
me dicati o n t
X
X
A d verse e ve nt u
X
X
E O R T C Q L Q -
C 3 0 v
X
X
X
X
E O R T C I L 6 3 
(M C L patie nts 
o nl y )v
X
X
X
X
A b bre vi ati o ns: A E = a d verse e ve nt; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; a P T T = acti vate d partial t hr o m b o plasti n ti me; B U N = bl o o d 
urea nitr o ge n; C = c ycle; C L L = c hr onic l y m p h oc ytic le u ke mia ; C M V = c yt o me gal o vir us; C R = c o m plete res p o nse; C R F = case re p ort f or m; C Ri = c o m plete res p o nse 
wit h i nc o m plete he mat ol o gic rec o very;  D = d a y; D N A = de o x yri b o n ucleic aci d; E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O n c ol o g y Gr o u p; E D C =
Electr o nic Data Ca pt ure ; E O R T C I L-6 3 = E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Ite ms Li brar y 6 3; E O R T C Q L D -C 3 0 = E ur o pea n Or ga nizati o n 
f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire C 3 0; E O T = E n d of Treat me nt; F L C = free li g ht c hai n; GI = gastr oi ntesti nal; H b A 1c = he m o gl o bi n 
A 1c; H Bc A b = he patitis B c ore a nti b o d y; H Bs A b = he patitis B s urface a nti b o d y; H Bs A g -he patitis B s urface a nti ge n; H B V = he patitis B vir us; H C V = he patitis C 
vir us; HI V = h u ma n i m m u n o deficie nc y vir us; I C F = i nf or me d c o nse nt f or m; I N R = i nter nati o nal n or malize d rati o; L D H = lactate d e h ydr o ge nase; L T F U = L o n g -ter m 
F oll o w - u p; M C L = ma ntle cell l y m p h o ma ; N H L = N o n -H o d g ki n L y m p h o ma ; P C R = p ol y merase c hai n reacti o n; P D = pr o gressi ve disease; P K = p har mac o ki netics; 
P R = partial res p o nse; P T = pr ot hr o m bi n ti me; P T T = partial t hr o m b o plasti n ti me; R B C = re d bl o o d cell; R N A = ri b o n ucleic aci d; S A E = seri o us a d verse e ve nt; S F U 
= safet y f oll o w -u p; S L L = s mall l y m p h oc ytic l y m p h o ma; S P E P = ser u m pr otei n electr o p h oresis; W B C = w hite bl o o d cell ; W M = Wal de nstr ö m macr o gl o b uli ne mia .
*
Certai n pr oce d ures t hat were o btai ne d as part of t he patie nt’s sta n dar d care pri or t o pr o vi di n g i nf or me d c o nse nt f or t his st u d y  (i.e., he mat ol o g y, i ma gi n g), ma y 
be utilize d f or scr ee ni n g or baseli ne p ur p oses pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria . I n Ta ble 7. 1 , if res ults are n ote d as re q uire d pri or t o 
starti n g L O X O-3 0 5, res ults of t hese st u dies ma y be re q uire d bef ore patie nts ma y be officiall y e nr ol le d.
* * E n d of Treat me nt ( E O T) assess me nts a n d pr oce d ures will be c o n d ucte d wit hi n 7 da ys of t he last d ose or  the decisi o n t o ter mi nate treat me nt. If la b testi n g is 
perf or me d ≤7 da ys pri or t o E O T, t o re peat testi n g d oes n ot nee d t o occ ur o n E O T.   It is n ot a n a d diti o nal visit, w h ic h ma y ha p pe n i n sc he d ule d visit .
N ote:  St u d y c o n d uct d uri n g e xce pti o n al circ u mst a nces ple ase refer t o A p pe n di x O .

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 5 6
L Y 3 5 2 7 7 2 7
a.
All c o n diti o ns o n g oi n g a n d rele va nt past s ur gical a n d me dical hist or y s h o ul d be c ollecte d. Mali g na nc y hist or y s h o ul d be c ollecte d re gar di n g disease u n der 
st u d y as well as a n y hist or y of ot her mali g na nc y o n t he a p pr o priate C R F.  
b.
P h y sical e xa mi nati o n i ncl u des ne ur ol o gical e xa m i nati o n, re vie w of rele va nt s yste ms, hei g ht a n d wei g ht at Scree ni n g a n d C 1 D 1 ( wit hi n 3 da ys). S ym pt o m -
directe d p h ysical e xa mi nati o n i ncl u di n g wei g ht s h o ul d be perf or me d at a p pr o priate re g ular ti me p oi nts of disease assess me nt.
c.
S y st olic a nd diast olic bl o o d press ure, heart rate ( p ulse is acce pta ble if patie nts are n ot u n der car diac arr yt h mias), res pirat or y r at e, a n d b o d y te m perat ure.   
•
F or vital si g ns assesse d at P K ti me p oi nts , vital si g ns i ncl u di n g wei g ht s ho ul d be c o n d ucte d pri or t o act ua l P K bl o o d sa m pli n g pr e-d ose (i nitial d ose) 
( u p t o 4 h o urs pre-d ose, as cl ose t o d osi n g as p ossi ble is preferre d) , a n d o n C 1 D 1 a n d C 1 D 8 vital si g ns s ho ul d als o be c o n d ucte d p ost -d ose at 2 h o urs
( ± 1 5 mi n utes).
• 
For  vital si g ns assesse d at n o n-P K ti me p oi nts : pr e-d ose ( u p t o 4 h o urs pre -d ose, as cl ose t o d osi n g as p ossi ble is preferre d)
d.
Tri plicate E C Gs perf or me d at least 5 mi n utes a part a n d wit hi n 1 da y s h o ul d be perf or me d d uri n g Scree ni n g a n d d uri n g C 1 D 1 a n d C 1 D 8 at t he f oll o wi n g ti me 
p oi nts: pre - d ose (i nitial d ose) ( u p t o 4 h o urs pre -d ose), 2 a n d at 4 h o urs p ost -d ose ( ± 1 5 mi n utes). I n a d diti o n, si ngle E C G s h o ul d be o btai ne d at 2 h o urs p ost -
d ose ( ± 1 5 mi n utes) o n D 1 of e ver y ot her c ycle of C 2 t hr o u g h C 1 2 . A d diti o n al E C Gs m a y  be perf or me d if cli nicall y i n dicate d. If a n u nsc he d ule d E C G is 
d o ne at a n y  ti me a n d a ne w, cli nicall y si g nifica nt a bn or malit y is i de ntifie d, a n electr ol yte pa nel (i.e., calci u m, ma g nesi u m, a n d p otassi u m) m ust be d o ne t o 
c oi nci de wit h t he E C G t esti n g. If a cli nicall y si g nifica nt arr h yt h mia is detecte d, cli nical details m ust be ca pt ure d i n E D C a n d/ or s u b mitte d as re q ueste d a n d 
re q uire d b y s p o ns or. Q Tc F will be calc ulate d usi n g Fri dericia’s F or m ula (refer t o Secti o n 4. 2 , E xcl usi o n Criteri o n 2 0).
e.
He mat ol o g y i ncl u des he m o gl o bi n, h e mat ocrit, R B C c o u nt, W B C c o u nt, platelet c o u nt, perce nt or a bs ol ute W B C c o u nt differe ntial ( ne utr o p hils, l y m p h oc ytes, 
e osi n o p hils, bas o p hils, a n d m o n oc ytes). F or W M a n d C L L / S L L patie nts, bl o o d sa m ples s h o ul d als o be pr o vi de d f or ce ntral assess me nt o n C 1 D 1, ± 7 da ys of 
eac h ra di ol o gic disease assess me nt a n d at disease pr o gressi o n. Scree ni n g res ults perf or me d wit hi n 7 da y s of C 1 D 1 ar e acce pta ble as C 1 D 1 res ults. Please 
e nter t he data c orrectl y i n t he C R F.
f.
C he mistr y fr o m plas ma or ser u m i ncl u des s o di u m, p otassi u m, c h l ori de, gl uc ose, B U N/ urea, creati ni ne, calci u m, ma g nesi u m, p h os p h or us, t otal bilir u bi n, 
direct bilir u bi n, t otal pr otei n, al b u mi n, A L T, A S T, al kali ne p h os p hatase, ga m ma -gl uta m yl tra nsferase, creati ne ki nase, L D H, ur ic aci d/ urate.  Li pase s h o ul d 
be perf or me d wit h D 1 bl o o d c he mistries f or eac h c ycle , C y cl e 1- 1 2. Scr ee ni n g res ults perf or me d wit hi n 7 da ys of C 1 D 1 are acce pta ble as C 1 D 1 res ults.
g.
C oa g ulati o n pa nel i ncl u des a P T T a n d P T (I N R).
h.
Ur i nal ysis s h o ul d i ncl u de c ol or, a p peara nce, s pecific gr a vit y, p H, gl uc ose, bilir u bi n, ket o nes, occ ult bl o o d, pr otei n, le u k oc ytes, nitrites, a nd ur o bili n o ge n. 
Scree ni n g res ults perf or me d wit hi n 7 da ys of C 1 D 1 are acce pta ble as C 1 D 1 res ults.
i.
All w o me n w h o are n ot p ost me n o pa usal (a n d 2 years of n o n -t hera p y-i n d uce d a me n orr hea) or s ur gicall y sterile will ha ve a ser u m pre g na nc y test at Scree ni n g 
wit hi n 7 da y s bef ore C y cl e 1 D a y 1 ( C 1 D 1). I n a d diti o n, f or w o me n of c hil d beari n g p ote ntial , a s er u m or uri ne pre g na nc y test m ust be perf or me d pri or t o 
treat me nt o n Da y 1 of eac h s u bse q ue nt c ycle of st u d y treat me nt.
j.
Patie nts wit h a p ositi ve HI V test are e xcl u de d fr o m st u d y partici pati o n. If He p B or C testi n g i n dicates ac ute or c hr o nic i nfecti o n or reacti vati o n of i nfecti o n, 
o btai n viral l oa d (e. g., q ua ntitati ve H B V -D N A, H C V -R N A) a n d o btai n c o ns ultati o n w it h a p h ysicia n wit h e x pertise i n ma na ge me nt of acti ve i nfecti o n a n d 
o nl y  patie nts meet t he eli gi bilit y criteria 2 4 ca n be e nr olle d. Eit her C M V P C R or a nti ge n tests s ho ul d be perf or me d d uri n g scree ni n g t o r/ o acti ve viral 
i nfecti o n. Refer t o Secti o n s 6. 3. 2 a n d 6. 3. 3 f or all o we d a n d pr o hi bite d c o nc o mita nt me dicati o ns, res pecti vel y, w h ic h s h o ul d be s hare d wit h t he c o ns ulta nt 
p h y sicia n.
k.
A n o n y mize d/re dacte d pat h ol o g y re p ort(s) c o nfir mi n g hist ol o gic dia g n osis a n d t he stat us of a n y kn o w n bi o mar kers (e. g., FI S H, I G V H, p 5 3, kar y ot y pe f or 
C L L / S L L, M Y D 8 8, C X C R 4 f or W M, Ki 6 7 stai ni n g f or MC L) s h o ul d be s u b mitte d.  I n patie nts wit h M C L, d oc u me ntati o n of c ycli n D 1 o vere x pressi o n
a n d/ or t( 1 1; 1 4) p ositi ve stat us m ust be pr o vi de d eit her as a pat h ol o g y re p ort fr o m a n yti me i n t he patie nt’s past or fr o m c urre nt tiss ue testi n g. Patie nts ma y n ot 
be e nr olle d wit h o ut d oc u me ntati o n of C ycli n D 1 a n d / or t( 1 1; 1 4) stat us. I n patie nts wit h W M, d oc u me ntati o n of M Y D 8 8 m utati o n m ust be pr o vi de d eit her as 
a pat h ol o g y re p ort fr o m t he patie nt’s past hist o r y or fr om c urre nt tiss ue testi n g. Patie nts wit h W M ma y  n ot be e nr olle d wit h out d oc u me ntati o n of M Y D 8 8 
m utati o n.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 5 7
L Y 3 5 2 7 7 2 7
l.
At st u d y e ntr y, ade q uate tiss ue sa m ple (l ym p h n o de/t u m or bi o ps y is pr eferre d) ) at scree ni n g is re q uire d f or patie nts e nr olle d i n C o h ort 1 f or ce ntral pat h ol o gy 
re vie w, G ui da nce is pr o vi de d i n t he La b orat or y Ma n ual a n d A p pe n di x K of Pr ot oc ol. 
•
F or M C L patie nt, tiss ue sa m ples m ust i ncl u de u p t o 1 0 u nstai ne d sli des or re prese ntati ve secti o ns of arc hi ve d paraffi n bl oc k f or Ce ntral Pat h ol o g y 
re vie w.
•
If t u m or sa m ple ca n n ot be o btai ne d safel y, t he patie nt ma y be e nr olle d i n C o h ort 3 if ot her eli gi bilit y criteria has bee n c hec ke d.
F or Ce ntral Pat h ol o g y re vie w, t he site s h o ul d als o s u b mit a de- i de ntifie d s ur gical pat h ol o g y re p ort of t he patie nt’s or i gi nal dia g n osis of l ym p h o ma a n d 
a ncillar y st u dies w hic h were use d t o esta blis h t he ori gi nal dia g n osis s uc h as fl o w c yt o metr y,  i m m u n o hist oc he mistr y, FI S H, c yto ge netics, or m olec ular st u dies.
m.
F or C L L / S L L, W M, i n d ole nt N H L, a n d selecte d cases of hi g h- gr a de N H L, baseli ne b o ne marr o w as pirate a n d/ or bi o ps y is re q uire d u nless was alrea d y d o ne 
after t he last treat me nt or w h ile pr o gressi n g o n t he m ost rece nt a n d wit hi n 9 0 da ys of Scree ni n g.  B o n e marr o w bi o psies perf or me d w hile still recei vi n g t he 
m ost rece nt treat me nt are all o we d if t he patie nt was pr o gressi n g at t he ti me of t he b o ne marr o w bi o ps y. A de q uate a m o u nt of sa m ples, fres h or arc hi ve d, m ust 
be a vaila ble as defi ne d i n t he La b orat or y Ma n ual f or ce ntral baseli ne assess me nt. Refer t o Secti o n 7. 4 A p pe n di x K a n d t he La b orat or y Ma n ual f or g ui da nce 
re gar di n g re q uire me nts f or sa m ple s u b missi o n base d o n hist ol o g y.  Patie nts wit h ot her res p o nse assess me nts c o nsiste nt wit h C R ma y nee d t o u n der g o b o ne 
marr o w bi o ps y a n d/or as pirati o n i n or der t o c o nfir m C R (refer t o Secti o n 7. 4 a n d A p pe n di x K ). All M C L patie nts w h ose ot her res p o nse assess me nt are 
c o nsiste nt wit h C R a n d k n o w n b o ne marr o w i n v ol ve me nt at baseli ne m ust u n der g o a b o ne marr o w bi o ps y i n or der t o c o nfir m C R.
n.
F or C L L / S L L patie nts, T -cell, B-cell a n d N K cell s u bsets a n d a bs ol ute B-cell c o u nt, t o be assesse d ce ntrall y; l ocal assess me nt is o pti o nal.
o.
F or W M patie nts a n d ot h e r patie nts if M-pr otei n k n o w n t o be prese nt at baseli ne, s ho ul d be assesse d l ocall y a n d sa m ples pr o vi de d f or ce ntral assess me nt. A 
se parate testi n g of ser u m t otal pr otei n s h o ul d als o be assesse d ce ntrall y f or hel pi n g esta blis h t he re p ort.
p.
Refer t o Secti o n 7. 8 a n d A p pe n di x A , A p pe n di x B , a n d A p pe n di x C f or s pecific ra di ol o gic disease assess me nt g ui deli nes.  In vesti gat ors m a y  co n d uct a n 
i nitial t u m or e val uati o n o n C 2 D 1 ( ± 7 da ys) ( o pti o nal base d o n cli nical i n dicate d) a n d a c o nfir mat or y t u m or e val uati o n a mi ni m u m of 4 wee ks ( C 3 D 1 ± 7 
da y s) after t he first t u m or e val uati o n if c o nsiste nt wit h l ocal re g ulat or y aut h orit y re q uire me nts. At baseli ne i ma gi n g s h o ul d i ncl u de c h est, a b d o me n, a n d 
pel vis, a n d ot her areas wit h diseas e i n v ol ve me nt. F oll o w -u p i ma gi n g i ncl u des c h est, a b d o me n, pel vis a n d a n y areas k n o w n t o ha ve disease i n v ol ve me nt at 
baseli ne. Ot her areas s uc h as t he nec k, hea d a n d e xtre mities m a y  be i ma ge d if disease i n v ol ve me nt is s us pecte d. F or patie nts (e. g., C L L or  W M) wit h 
d oc u me nte d disease i n v ol vi n g bl o o d/ b o ne marr o w b ut n o d oc u me nte d baseli ne ra di o gra p hic fi n di n gs a n d w here ra di ol o g y is n ot r eq uire d f or r outi ne res p o nse 
assess me nt, i ma gi n g is t o be perf or me d e ver y 6 c ycles (i.e., e n d of c ycle 6, e n d of c ycle 1 2) f or t he d urati o n of st u d y treat me nt.  Cli nical P D s ho ul d be 
assesse d wit h ra di o gra p hic i ma gi n g u nless m ost rece nt i ma gi n g was perf or me d wit hi n 2 8 da ys of cli nical P D.
q.
Refer t o Ta ble 7. 2 . 
r.
Patie nts will be f oll o we d f or s ur vi val stat us, date of pr o gressi o n, a n d s u bse q ue nt a ntica ncer t hera p y(ies) b y tele p h o ne or ot h e r met h o d.
s.
I ncl u des L O X O-3 0 5 d osi n g.
t.
C o nc o mita nt me dicati o ns, i ncl u di n g o n g oi n g me dicati o n(s) pl us t h ose a d mi nistere d wit hi n 1 4 da ys pri or t o t he pla n ne d start of treat me nt.
u.
A Es s h o ul d be rec or de d fr o m t he ti me t hat writte n i nf or me d c o nse nt has bee n o btai ne d t hr o u g h t he S F U Visit. All S A Es s h o ul d be rec or de d be gi ns after t he
patie nt has si g ne d t he I C F a n d has recei ve d i n vesti gati o nal pr o d uct t hr o u g h 2 8 da ys after t he last d ose.  H o we ver, if a n S A E occ urs after si g ni n g t he I C F, b ut 
pri or t o recei vi n g i n vesti gati o nal pr o d uct, t he S A E s ho ul d be re p orte d t o t he s p o ns or as per S A E re p orti n g re q uire me nts a n d ti meli nes if it is c o nsi dere d 
reas o na bl y p ossi bl y relate d t o st u d y pr oce d ure. S A Es occ urri n g after t he S F U visit a n d j u d ge d b y t he in vesti gat or as relate d t o st u d y dr u g s h o ul d be re p orte d.
v.
Refer t o A p pe n di x M .
w.
Patie nts wit h M C L
i n C o h ort 1 wit h hist or y  or evi de nce of GI i n v ol ve me nt o n baseli ne assess me nt ma y re q uire a p pr o priate u p per a n d/ o r l o wer e n d osc o p y 
pr oce d ure (if it is cli nicall y safe) d uri n g scree ni n g wit h bi o ps y t o d oc u me nt i n v ol ve me nt at baseli ne. Patie nts wit h M C L i n C o h ort 1 w it h k n o w n or e vide nce 
of GI 
i n v ol ve me nt
(t hr o u g h cli nical, i ma gi n g or e n d osc o p y)
at baseli ne,
w h ose ot her disease assess me nts s u g gest C R 
m ust 
u n der g o 
Es o p ha g o gastr o d u o de n osc o p y a n d /or C ol o n osc o p y wit h ra n d o m se g me ntal bi o psies t o c o nfir m C R (if it is cli nicall y safe).
x.
If a patie nt disc o nti n ues st u d y treat me nt f or reas o ns ot her t ha n P D , wit h dra wal of c o nse nt or i nitiati o n of a ne w a ntica ncer t hera p y(ies), t he patie nt is re q uire d 
t o u n der g o t u m or assess me nt i n t he ti me wi n d o ws of L T F U u ntil P D (e ve n if P D occ urs after 2 years), wit h dra wal of c o nse nt, or i nitiati o n of a ne w a ntica ncer 
t hera p y(ies), utilizi n g t he sa me m o dalit y(ies) use d f or t he baseli ne i ma gi n g assess me nt.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 5 8
L Y 3 5 2 7 7 2 7
C CI

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 5 9
L Y 3 5 2 7 7 2 7
7. 1
St u d y Assess me nts
7. 1. 1
I nf or me d C o nse nt
P ati e nts must be a ble t o pr o vi de writte n i nf or me d c o nse nt a n d meet eli gi bilit y crit eria prior t o 
e nr o ll me nt. T he I C F m ust be si g ne d bef ore a n y pr ot oc ol -s pecifie d pr oce d ures are perf or me d 
e xce pt as n ote d i n Secti o n 7. 1. 2 .  A d dit i onal details are pr o vi de d i n S ect i on 1 0. 1. 3 .
7. 1. 2
Scree ni n g
T he scree ni n g pr oce d ures m ust be c o n d ucte d wit hi n 2 8 da ys pri or t o C 1 D 1, u nless ot her wise 
n ote d. Patie nts w h o ca n n ot c o m plete t he pr oce d ures wit hi n t he scree ni n g wi n d o w a n d w h o d o 
n ot m eet t he crit eria for parti ci pat i on i n t his st u d y (scree n fail ure) ma y be rescree ne d aft er 
di sc ussi on wi t h a n d per missi on fr om t he Lill y C R P or desi g nee, a n d certai n scree ni n g 
pr oce d ures ma y  not nee d t o be re peate d wit h d oc u me nte d s p o ns or a p pr o val. C ertai n pr oce d ures 
(i.e., he mat olo g y , i ma gi n g) t hat were o btai ne d as part of t he patie nt’s sta n dar d care pri or t o 
pr o vi di n g i nf or me d c o nse nt f or t his st u d y , ma y be utilize d f or scree ni n g or baseli ne p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me 
fra me defi ne d i n t he Ta ble 7. 1 . T he res ults s h o ul d be rec or de d i n t he Scree ni n g set of C R Fs.
Scree ni n g tests ot her t ha n ra di o l og y  t hat are c o mplete d i n t he 7 da ys pri or t o start of st u d y  dr u g 
a d mi nistrati o n will be acce pte d as f ulfilli n g t he C 1 D 1 assess me nts; re peat testi n g o n C 1 D 1 is 
n ot necessar y  for t hi s sce nario a n d res ul ts s h o uld be rec or de d i n t he Scree ni n g set of C R Fs.
7. 1. 3
E nr oll me nt
E nr oll me nt pr oce d ures will be c o n d ucte d i n acc or da nce wit h t he Sc he d ule of Assess me nts 
(Ta ble 7 . 1). Patie nts w h o meet eli gi bilit y cri t eria o utli ne d i n Sect i on 4 will be e nr olle d i n t h is 
st u d y. T he in vesti gat or ma y  re peat q ualif yi n g la b orat or y tests a n d vit al si g ns/ E C Gs prior t o 
e nr o ll me nt a n d wit hi n scree ni n g wi n d o w, if a n o n- q ualif yi n g fi n di n g is c o nsi dere d a n err or, 
a n d/ or if a n ac ute fi n di n g is li kel y t o meet eli gi bilit y criteria o n re peat testi n g.
7. 1. 4
Me dic al a n d S ur gic al Hist ory, a n d De m o gr a p hics
All c o n ditio ns o n g oi n g a n d rel e va nt past s ur gical a nd me dical  hist or y s h o uld be c ollecte d. 
Me dical, s ur gical, a n d mali g na nc y hist or y , i ncl u di n g t he disease u n der st u d y as well as hist or y 
of a n y ot her mali g na nc y, dia g n osis dates, t ypes a n d pri or treat m e nts for t he m ali g na nc y, etc.
s h o uld be rec or de d o n t he a p pr o priate C R F. De m o gra p hics i ncl u di n g a ge, ge n der, race, a n d 
et h nicit y will be rec or de d.
7. 1. 5
P hysic al E x a mi n ati o n
P h ysical e xa mi nat i ons wil l be c o n d ucte d i n acc or da nce wit h t he Sc he d ule of Assess me nts 
(Ta ble 7. 1 ) a n d will i ncl u de b o d y  wei g ht, a n d hei g ht, ne ur ol o gical e xa mi nat i on a n d re vie w of 
r ele va nt s yste ms at Scree ni n g a n d C 1 D 1. Scree ni n g res ults o b tai ne d wit hi n 3 da ys of C 1 D 1 are 
acce pta ble as C 1 D 1 res ults. S y m pt o m -di recte d p h ysical e xa mi nati on ma y be p erf or m e d at ot her 
ti me p oi nts after Scree ni n g i n acc or da nce wit h t he Sc he d ule of Assess me nts ( Ta ble 7. 1) .

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7.1.6
Eastern Cooperative Oncology Group Performance Status
ECOG performance status will be assessed in all patients in accordance with the Schedule of 
Assessments (Table 7.1). The ECOG performance scale is provided in Appendix L. The ECOG 
performance status will assist in assessing how a patient's disease is progressing or responding, 
assessing how the disease affects the daily living abilities of the patient, and determining the 
appropriate treatment and prognosis.
7.1.7
Vital Signs
Vital signs will be measured pre-dose in accordance with the Schedule of Assessments (Table
7.1) and should include systolic and diastolic blood pressure, heart rate (pulse is acceptable if 
patients are not under cardiac arrythmias), respiratory rate, and body temperature.
At PK time points, vital signs particularly weight should be assessed as indicated in the 
Schedule of Assessments (Table 7.1), prior to actual PK blood sampling pre-dose (initial dose) 
(up to 4 hours pre-dose, as close to dosing as possible is preferred), and on C1D1 and C1D8 
vital signs should also be conducted post-dose at 2 hours (±15 minutes). At non-PK time points, 
vital signs should be assessed at pre-dose (up to 4 hours pre-dose, as close to dosing as possible 
is preferred).
7.1.8
Electrocardiograms
Twelve-lead resting ECGs will be performed in accordance with the Schedule of Assessments 
(Table 7.1). Triplicate ECG should be performed at least 5 minutes apart and within one day
during Screening, and during C1D1 and C1D8 at the following time points: pre-dose (initial 
dose) (up to 4 hours pre-dose), 2 and at 4 hours post-dose (±15 minutes). In addition, single 
ECG should be obtained at 2 hours post-dose (±15 minutes) on D1 of every other cycle of C2 
through C12. To minimize variability, it is important that patients are in a resting position for at
least 5 minutes prior to each ECG evaluation. Body position should be consistently maintained
for each ECG to prevent changes in heart rate. ECGs for each patient should be obtained from 
the same machine whenever possible. When ECGs coincide with PK draw days, ECGs should 
be performed before the PK blood draw. Any clinically significant changes in ECGs that occur 
during the study should be reported as an AE in the CRF.
We may request de-identified copies of the ECGs for adjudication. Sites are required to submit 
ECG tracings for sponsor review in these circumstances. 

Manually review ECGs to confirm accuracy. ECGs must be interpreted by a qualified 
physician (the investigator or qualified designee) at the site for immediate patient 
management. 

If the ECG is abnormal, 
o
Assess for all possible causes (concomitant medications, electrolyte abnormalities, 
underlying cardiac conditions). 
o
Clinical chemistry should be assessed and if electrolytes are abnormal, they should be 
repeated as indicated. Potassium should be ≥4 meq/L and less than ULN and 
magnesium and calcium should be within normal limits. 
o
Serial repeat ECG collection to ensure resolution should be conducted as clinically 

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appropriate 

If patients have an underlying bundle branch block (BBB), ECGs must be manually 
reviewed by a qualified physician and the QTc value must be corrected (utilizing locally 
approved correction factors) and this value should be entered into the CRF. 

If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing. 

If triplicate ECGs are obtained to confirm a Grade 3 AE (QTcF ≥501 msec or ≥ baseline 60 
msec) as outlined in the NCI CTCAE v5.0 criteria, ECGs should be collected 1 minute 
apart.

Patients should be clinically monitored for symptoms of cardiac arrhythmias (e.g., 
palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. ECG should be 
done as clinically indicated for assessment with electrolyte panel. If a clinically significant 
arrhythmia is discovered (e.g., atrial fibrillation/atrial flutter), the clinical circumstances 
surrounding the time of onset, if known (e.g., time/date of onset, activity and/or lifestyle 
changes/factors at the time of onset, associated symptoms, laboratory values) must be 
documented in the CRF.
7.1.9
Laboratory Tests
Local laboratories will be utilized for routine laboratory tests, for example, blood chemistries 
from serum or plasma, hematology, and urinalysis. For ≥Grade 3 laboratory toxicity, laboratory 
testing should be repeated at least once a week until levels normalize or return to approximate 
baseline levels.  Certain laboratory tests will also be assessed centrally depending on diagnosis 
at enrollment (e.g., complete blood count and lymphocyte subsets for CLL/SLL/WM patients, 
serum protein electrophoresis (SPEP) /immunofixation /serum free light chain
(FLC)/quantitative Igs for WM patients). Special assessments, such as PK studies, will be 
performed centrally. Additional guidance regarding testing and handling and processing of 
samples for central assessment is provided in Appendix K and the Laboratory Manual.

Hematology
For all enrolled patients: Hematology should be assessed locally in accordance with the 
Schedule of Assessments (Table 7.1) and should include assessment of the following: 
hemoglobin, hematocrit, RBC count, WBC count, platelet count, percent or absolute WBC 
count differential (neutrophils, lymphocytes, eosinophils, basophils, and monocytes).
For WM and CLL/SLL patients: Blood samples for central assessment should also be collected 
on C1D1, ±7 days of each radiologic disease assessment and at disease progression.

Blood Chemistries
Blood chemistries from serum or plasma should be assessed locally in accordance with the 
Schedule of Assessments (Table 7.1) and should include assessment of the following: sodium, 
potassium, chloride, glucose, blood urea nitrogen (BUN)/urea, creatinine, calcium, magnesium, 
phosphorus, total protein, albumin, total bilirubin, direct bilirubin, ALT, AST, alkaline 
phosphatase, gamma-glutamyl transferase, creatine kinase, uric acid/urate, and LDH. Lipase 
should be performed with D1 laboratory tests for each cycle, Cycles 1 through 12.  Screening 
results performed within 7 days of C1D1 are acceptable as C1D1 results.

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
Coagulation
The coagulation panel should include aPTT and PT (INR) and should be assessed locally during 
Screening and then only as clinically indicated.  If PT measured in seconds is not available, then 
INR alone will suffice.

Urinalysis
Urinalysis should be assessed locally in accordance with the Schedule of Assessments (Table
7.1) and should include color, appearance, specific gravity, pH, glucose, bilirubin, ketones, 
occult blood, protein, leukocytes, nitrites, and urobilinogen.

Pregnancy Testing
For appropriate patients: Pregnancy testing (serum or urine) must be conducted locally in 
accordance with the Schedule of Assessments (Table 7.1). Pregnancy reporting information is 
provided in Section 9.4. All women which is defined as following menarche and who are not 
postmenopausal (and 2 years of non-therapy-induced amenorrhea) or surgically sterile will have 
a serum pregnancy test at Screening. In addition, for women of childbearing potential, a serum 
or urine pregnancy test must be performed prior treatment on Day 1 of each subsequent cycle of 
study treatment. If any urine pregnancy test is positive, study treatment will be delayed until the 
patient pregnancy status is confirmed by a serum pregnancy test. If serum pregnancy test is 
positive, the patient will be permanently discontinued from study treatment.

Viral testing: HIV, CMV, Hepatitis B/C
Viral testing should be assessed at baseline locally in accordance with the Schedule of 
Assessments (Table 7.1) and should include testing for HIV, cytomegalovirus (CMV) 
(quantitative polymerase chain reaction [PCR] or antigenemia), hepatitis B (hepatitis B surface 
antigen [HBsAg], hepatitis B surface antibody [HBsAb], and total hepatitis B core antibody 
[HBcAb]) and hepatitis C virus (HCV) antibody serology. Patients with a positive HIV test are 
excluded from participation in the trial due to potential drug-drug interactions between anti-
retroviral medications and LOXO- 305 and risk of opportunistic infections with both HIV and 
approved BTK inhibitors. If other testing indicates acute or chronic infection or reactivation of 
infection, obtain viral load (e.g., quantitative hepatitis B virus [HBV]-DNA, HCV- RNA, CMV-
DNA). Patients with detectable HBV DNA and controlled disease may be permitted on therapy 
with sponsor approval. Concurrent viral suppressive treatment will be required for patients with 
detectable HBV DNA (refer to Sections 6.3.2 and 6.3.3 for allowed and prohibited concomitant 
medications which should be shared with the consultant physician) and undergo regular 
monitoring of viral load during treatment and for at least 12 months after study treatment 
completion. Patients with history of HCV infection who have completed viral suppressive 
therapy and have a viral load below the limit of quantification are allowed. Either CMV PCR or 
antigen tests should be performed during screening to r/o active viral infection.

Lymphocyte Subsets
For CLL/SLL patients: Lymphocyte subsets should be assessed centrally in accordance with the 
Schedule of Assessments (Table 7.1) and should include T-cell, B-cell and NK cell subsets and 
absolute B-cell count. Blood samples for local assessment can be done per investigator 
discretion.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 6 3
L Y 3 5 2 7 7 2 7

S P E P, Ser u m I m m u n ofi xat i on, Ser u m F L C, Q ua ntitati ve I m m u n o gl o b uli ns , T otal  Pr otei n
F or W M patie nts a n d a n y patie nts w here a para pr otei n is k n o w n : l ocal a n d ce ntral assess me nt 
of  S P E P, ser u m i m m u n ofi xati on, ser u m F L C, a n d q ua nt itati ve i m m u n o gl o b uli ns s h o ul d be 
assesse d i n W M patie nts (a n d ot her patie nts if M- pr otei n k n o w n t o be prese nt at baseli ne) i n 
acc or da nce wit h t he Sc he d ule o f Assess me nts ( Ta ble 7 . 1). A se parate testi n g of ser u m t otal 
pr otei n s h o uld als o be assesse d ce ntrall y f or hel pi n g esta blis h t he re p ort .
7. 2
P h ar m ac o ki netics
P K sa m ples s h o ul d be c o llecte d i n acc or da nce wit h t he Sc he d ule of Assess me nts (Ta ble 7. 2 ). 
A d dit i onal P K assess me nts ma y be c o n d ucte d i n patie nts w he n c o nsi dere d necessar y b y t he 
in vesti gat or t o u n dersta n d e x p os ure i n relat i ons hi p t o p ossi ble safet y or efficac y fi n di n gs or if 
t her e is a c ha n ge t o t he f or m ulat i on of L O X O -3 0 5 a d mi nistere d.
F or C 1 D 1, sa m pli n g s h o ul d be ti me d t o i nit ial start of L O X O-3 0 5. F or sa m pli n g after C 1 D 1, 
sa m pli n g s h o ul d be ti me d t o t he L O X O -3 0 5 d ose ta ke n f or t he da y.
T he pl as ma c o nce ntrati o n of L O X O -3 0 5 will be deter mi ne d wit h a vali date d bi oa nal yt ical assa y 
a n d use d t o calc ulate P K para meters as descri be d i n Secti o n 8. 3. 4 . T hese para meters will be 
use d t o assess li nearit y of  e x p os ure a n d acc u m ulati o n of dr u g e x p os ure wit h ti me.
C o nce ntrati o ns of L O X O -3 0 5 m a y also be use d f or p o p ulat i on- P K  a nal yses, t o be re p orte d i n a 
se paratel y re p ort b y t he sp o ns or.
7. 3
Tele p h o ne F oll o w -u p
T he site will c o ntact t he patie nt b y  t ele p h o ne i n acc or da nce wit h t he Sc he d ule of Assess me nts 
(Ta ble 7 . 1) t o assess f or L O X O - 3 0 5 t olera bilit y, c o nti n uati on of st u d y  dr u g , a n d w het her t he 
pati e nt nee ds t o ret ur n t o cli nic earlier t ha n pla n ne d. If n ot t olerati n g t he dr u g well, t he patie nt 
s h o uld be see n at l east e ver y 1 4 da ys t o assess A Es, a n d t he patie nt s h o ul d be c o ntacte d 
re g ularl y t o assess A E stat us.
7. 4
Ce ntr al T u m or S a m ple S u b missi o n ( Peri p her al Bl o o d, B o ne M arr o w, Tiss ue)
A de q uate tiss ue sa m ples at scree ni n g are re q uire d fr om pat ient s e nr olle d i n C o h ort 1 f or ce ntral 
pat h ol o g y  re vie w t o be p erf or m e d retr os pecti vel y.  P atie nts wit h ina de q uate ti ss ue sa m ple 
a vaila bilit y ma y st ill be e nr o lle d i n C o h ort 3 if ot her eli gi bility criteria have bee n c hec ke d .  
C CI

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For patients enrolling with MCL, nodal tissue is preferred (vs marrow) and must include up to 
10 unstained slides (or representative sections of archived paraffin block).  De-identified 
surgical pathology reports of the patient’s diagnosis of lymphoma and ancillary studies, such as 
flow cytometry, immunohistochemistry, FISH, cytogenetics, or molecular studies, which were 
used to establish the diagnosis are also requested.
For MCL: for Screening, bone marrow biopsy is required for baseline assessment, and patients 
in Cohort 1 with known or evidence of GI involvement appropriate upper and/or lower 
endoscopy may be performed if it is clinically safe for baseline assessment and if not performed 
within 42 days of enrollment. Adequate sample as Lab Manual is required to submit for central 
assessment.
For response assessment: Bone marrow biopsy should be done as appropriate for confirmation 
of CR if known disease involvement at baseline.  Other assessments suggest CR, 
esophagogastroduodenoscopy and colonoscopy with random segmental biopsies is required, if 
clinically safe, for confirmation of CR in Cohort 1 MCL patients with known GI involvement at 
baseline. Adequate sample as Lab Manual is required to submit for central review.  Bone 
marrow and endoscopy for local response assessment at the time points specified in Table 7.1
and Appendix K are also required.
For CLL/SLL: for Screening, peripheral blood and bone marrow biopsy with aspirate are 
required for baseline tumor assessment, and adequate sample as  Lab Manual required also 
should submit for central assessment.
For response assessment: Peripheral blood is required. Bone marrow biopsy and aspiration is 
required for confirmation of CR and should be done in appropriate settings where all other 
assessments suggest CR and adequate sample as Lab Manual is required to submit for central 
review. Peripheral blood and bone marrow for local response assessment at the time points 
specified in Table 7.1 and Appendix K are also required.
For WM: for Screening, peripheral blood and bone marrow biopsy with aspirate are required
for baseline assessment and adequate sample as Lab Manual is required to submit for central 
assessment. 
For response assessment: Peripheral blood is required. Bone marrow biopsy and aspiration is 
required for confirmation of CR and should be done in appropriate settings where all other 
assessments suggest CR and adequate sample as Lab Manual is required to submit for central 
review. Peripheral blood and bone marrow for local response assessment at the time points 
specified in Table 7.1 and Appendix K are also required.
For indolent NHL (e.g., MZL, follicular lymphoma [FL]): for Screening: Bone marrow biopsy 
is required for marrow involvement assessment and adequate sample as Lab Manual required 
also should submit for central assessment.
For response assessment: Bone marrow biopsy is required for confirmation of CR and should be 
done in appropriate settings if known disease involvement at baseline and all other assessments 
suggest CR and adequate sample as Lab Manual required also should submit for central 
assessment.

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For non-MCL high grade NHL (e.g., diffuse large B cell lymphoma [DLBCL]): For Screening: 
Bone marrow biopsy is required only if clinical suggestion of marrow involvement is noted, i.e., 
unexplained cytopenia, and adequate sample as Lab Manual required also should submit for 
central assessment.  
For response assessment: Bone marrow biopsy should be done as appropriate for confirmation 
of response assessment only if known disease involvement at baseline; per Lugano staging 
criteria, positron emission tomography (PET) scan assessment of marrow response is acceptable.  
7.5
Pathology and Molecular Reports
Anonymized/redacted pathology report(s) confirming histologic diagnosis and relevant 
biomarkers (e.g., FISH, IGVH, p53, karyotype for CLL/SLL, MYD88, CXCR4 status for WM, 
Ki67 staining for MCL) should be submitted. For patients with MCL, documentation of Cyclin 
D1 overexpression and/or t(11;14) positive status must be provided either from any time in the 
patient’s history or from current biopsy studies in order for enrollment to proceed. For patients 
with WM, documentation of MYD88 mutation must be provided either from any time in the 
patient’s history or from current biopsies studies in order for the patient to proceed.
7.6
Bone Marrow Aspirate and Biopsy
For patients enrolled with CLL/SLL, WM, low grade NHL, and selected high grade NHL (refer 
to Section 7.4): A bone marrow aspirate and/or biopsy should be collected during Screening, for 
confirmation of CR and (optional) at disease progression in accordance with the Schedule of 
Assessments (Table 7.1). All MCL patients, whose other response assessments are consistent 
with CR and known disease involvement at baseline, must undergo bone marrow biopsy to 
confirm CR.  Samples for central assessment should also be collected in accordance with the 
Schedule of Assessments (Table 7.1) and outlined in Section 7.4 “Central Tumor Sample 
submission”. If a bone marrow biopsy and/or aspiration was done after the last treatment or 
while progressing on the most recent treatment and within 90 days of Screening and samples are 
available of sufficient quality and quantity for central analysis, these do not need to be repeated 
during Screening. Guidance on sample collection and timing is provided in Appendix K and the 
Laboratory Manual.
7.7
Gastrointestinal Endoscopy
For MCL patients in Cohort 1 with known or evidence of GI involvement appropriate upper 
and/or lower endoscopy may be performed if it is clinically safe for baseline assessment, if not 
performed within 42 days of enrollment. For enrolled patients with MCL with known GI 
involvement (through clinical, imagine or endoscopy) at baseline in Cohort 1, who are in 
radiographic and bone marrow CR, esophagogastroduodenoscopy and colonoscopy with random 
segmental biopsies must be performed as appropriately, to evaluate for GI involvement with 
MCL and to confirm CR.
7.8
Radiologic Disease Assessment
Radiologic disease assessment will be conducted by the investigator in accordance with the 
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same method consistently for an individual patient throughout the study.  For NHL, the 
preferred imaging is PET/CT, and appropriate method in accordance with Lugano guidance 
should be selected based on patients pathologic diagnosis, FDG avidity and lesion location etc..  
For patients with NHL, baseline scans should assess the chest, abdomen, and pelvis.  Other areas 
such as the neck, head and extremities should be scanned should there be known disease present.  
Follow up CT scans may be limited to chest, abdomen and pelvis as well as areas of known 
measurable and non-measurable disease. Assessments of both measurable and non-measurable 
disease will be made by the investigator using criteria as appropriate to cancer type; SLL 
response should be assessed by IWCLL criteria. The following Appendices should be referred 
to for specific radiologic disease assessment information:

Appendix A
Lugano Classification of Response in Non-Hodgkin Lymphoma

Appendix B
Chronic Lymphocytic Leukemia Response Assessment (IWCLL)

Appendix C
Waldenström Macroglobulinemia Response Assessment (IWWM)
For patients (e.g., CLL or WM) with documented disease involving blood/bone marrow but no 
documented baseline radiographic findings and where radiology is not required for routine 
response assessment, imaging is to be performed every 6 cycles (i.e., end of Cycle 6, end of 
Cycle 12) for the duration of receipt of study treatment.  If tumor involvement is identified 
during routine assessments, then the radiographic assessment schedule will revert to the standard 
schedule.
In addition, investigators may conduct an initial tumor evaluation on C2D1 (±7 days) (optional 
based on clinical indicated) and a confirmatory tumor evaluation a minimum of 4 weeks 
(C3D1±7d) after the first tumor evaluation, if consistent with local regulatory authority 
requirements.
Clinical PD should be assessed with radiographic imaging unless most recent imaging was 
performed within 28 days of clinical PD.
If patient terminates treatment prior to scheduled disease assessments, the patient should have 
assessment done at the EOT visits (does not need to be repeated if performed within 2 weeks 
prior to the EOT visits, or if tumor progression was previously determined).  
Patients who are unable to undergo CT scans with contrast due to allergy to contrast dye, may 
substitute magnetic resonance imaging (MRI) with gadolinium or appropriate method per 
investigator discretion and should discuss with sponsor.
7.9
Survival Status
Patients will be followed for survival status, date of progression, and subsequent anticancer 
therapy(ies) by telephone or other method.
7.10 Study Drug and Dosing Diary
Study drugs taken orally should be administered in accordance with the Schedule of 
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recording of LOXO-305 dosing.
7.11 Concomitant Medication
Concomitant medications should be recorded in accordance with the Schedule of Assessments 
(Table 7.1).
All medications that were used from 14 days prior to the planned start of study drug or from 
Screening (whichever is shorter) through SFU (at least 28 days [+7 days] after the last dose of 
study drug) will be recorded in the CRF. These are to include prescription and nonprescription 
medications, transfusions, vitamins and nutritional supplements, and other remedies. Excluded 
prior medications are excluded via the eligibility criteria (Section 4.2). Additional guidance 
regarding concomitant medications is provided in Section 6.3.
7.12 Adverse Events/Serious Adverse Events
Adverse events should be recorded in accordance with the Schedule of Assessments (Table 7.1) 
and Section 9.
7.13 Patient-reported Outcomes (PRO) Assessments
The European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (EORTC QLQ-C30), the supplementary ‘cancer-related symptom’ 
assessments for MCL (European Organization for Research and Treatment of Cancer Items 
Library 63 [EORTC IL63]) (refer to Appendix M) will be administered in accordance with the 
Schedule of Assessments (Table 7.1). Each assessment should be performed as early as possible 
during the clinic visit, before the patient interacts extensively with staff and before the patient 
learns the results of their restaging.  Physicians and staff should refrain from viewing results 
prior to completion of the clinic visit. PRO assessments will be administered according to 
Schedules of Assessments in Table 7.1 in countries where the questionnaires have been 
translated into the native language(s) of the region. Only patients fluent in an available 
translated language should complete the questionnaires.
Although individual patients may vary in their response time, 2 recent publications have 
evaluated survey completion times. One study among patients with advanced cancer suggests 
that a 20-item assessment (approximately half of the 38-39 total items to be completed in this 
study) can be completed in an average of less than 4 minutes when administered via paper 
(Bennett et al. 2016). In a second study, 67 items (28-29 more than in this study) were 
completed in an average of 15 minutes; 100% of patients reported the completion time as “about 
right”, 79% were willing to answer more questions (Girgis et al. 2017).
7.14 Central Collection of Radiographic Studies and Samples
Baseline screening radiographic studies and all subsequent radiographic studies will be collected 
for independent radiological review.
Baseline and subsequent samples (peripheral blood, bone marrow aspiration, biopsy and/or 
tissue samples) required for response assessment according to disease-defined criteria will be 
collected.

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7.15 End of Treatment
Within 7 days after last dose of study drug or at the time of the decision to terminate treatment, 
the EOT assessments and procedures will be conducted in accordance with the Schedule of 
Assessments (Table 7.1). If lab testing is performed ≤7 days prior to EOT, repeat testing does 
not need to occur on EOT. 
7.16 Safety Follow-up
The safety follow-up assessments will be conducted in accordance with the Schedule of 
Assessments (Table 7.1). Safety follow-up procedures may be performed as part of the EOT 
visit if the latter was performed at least 28 days after final dose of the last cycle.
7.17 Long-Term Follow-up
The LTFU assessments and procedures will be conducted in accordance with the Schedule of 
Assessments (Table 7.1). After treatment discontinuation, LTFU will occur approximately 
every 3 months (±1 month) for up to 2 years and every 6 months (±2 month) thereafter, until the 
patient experiences PD, withdraws consent for further participation, is lost to follow-up, has 
died, or close of the study.
Assessments may include: subsequent anticancer therapy(ies) and survival status. LTFU may be 
conducted by phone. For any patient who is lost to follow-up, the study site will attempt to 
ascertain survival information via public database search. If survival status still cannot be 
ascertained, patients will be considered lost to follow-up and will be censored appropriately.
If a patient discontinues study treatment for reasons other than PD, withdrawal of consent or 
initiation of a new anticancer therapy(ies), the patient is required to undergo disease assessment 
as specified in Appendix A, Appendix B, and Appendix C until PD (even if PD occurs after 2 
years), withdrawal of consent, or initiation of a new anticancer therapy(ies), utilizing the same 
modality(ies) used for the baseline imaging assessment.

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8.
S T A TI S TI C A L C O N SI D E R A TI O N S
A f ull Statistical A nal ysis Pla n ( S A P) will pr o vi de s pecific details o n t he a nal ytical met h o ds a n d 
data di s pla ys.
8. 1
A n al ysis P o p ul ati o ns
8. 1. 1
S afety P o p ul ati o n
T he safet y p o p ul at i on will be use d pri maril y  for t he a nal ysis of safet y data a n d will c o nsist of all 
e nr o lle d patie nts w h o recei ve 1 or m ore d oses of L O X O - 3 0 5.
8. 1. 2
Pri m ary A n alysis Set
T he Pri mar y A nal ysis Set ( P A S) will be use d f or t he a nal ysis o f t u mor res p o nse a n d ot her 
efficac y-r elate d data of  C o h ort 1 a n d C o h ort 2 . 
T he P A S f or C o h ort 1 will i ncl u de all patie nts e nr olle d i n t his c o h ort w h o meet t he f o ll owi n g 
criteria:

Ce ntral  hist olo gi call y c o nfir me d n o n -blast oi d M C L wi t h n o C N S metastases a n d 
treated wit h pri or c he m oi m m u n ot hera p y a n d B T K i n hi bit or -c o nt ai ni n g re gi me n.

Meas ura ble disease at baseli ne as assesse d usi n g L u ga n o criteria

Recei ve d at least 1 d ose of st u d y dr u g
T he P A S f or C o h ort 2 will i ncl u de all patie nts e nr olle d i n t his c o h ort w h o meet t he f oll owi n g 
criteria:

C L L/ S L L pre vi o usl y  treate d wit h a B T K i n hi bit or

Meas ura ble disease at baseli ne as assesse d usi n g I W C L L

Recei ve d at least 1 d ose of st u d y dr u g
Detail s of a nal ysis sets will be pr o vi de d i n S A P.
8. 2
Deter mi n ati o n of S a m ple Size
C CI

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T he decisi o n t o f urt her i n vest i gate certai n c o h orts will be 
base d o n c o m pre he nsi ve e val uat i on of t he ris k -be nefit pr ofile. 
Ta ble 8. 1 pr o vi des g ui da nce f or i nter pretati o n of t he treat me nt effect f or eac h c o h ort base d o n 
t he o bser ve d O R R.
8. 3
St atistic al A n al yses
Stati stical a nal ysis of t his st u d y will  be t he res p o nsi bilit y of  Lill y or its desig nee.
All tests of treat me nt effects will be c o n d ucte d at a 2 -si de d alp ha le vel of 0. 0 5, u nless ot h er wise
state d. All CIs will be gi ve n at a 2 -si de d 9 5 % le vel, u nless ot her wise state d.
A n y c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol will re q ui re a n a me n d me nt
O N L Y if it c ha n ges a pri nci pal feat ure of t he pr ot oc ol.
A n y ot her c ha n ge t o t he data a nal ysis met h o ds descri be d i n t he pr ot oc ol, a n d t he j ustificati on f or
ma ki n g t he c ha n ge, will be descri be d i n t he S A P a n d cli nical st u d y re p ort ( C S R). 
T he ass u m pt i ons f or eac h statistical met h o d ma y be e val uate d. If t here is vi olati o n of
ass u m pt i ons, alter nat i ve statistical met h o ds ma y be use d. 
A d dit i onal e x plor at or y  a nal yses of t he data will be c o n d ucte d as dee me d a p pr o priate.
8. 3. 1
De m o gr a p hics a n d B aseli ne C h ar acteristics
Descri pt i ve s u m maries of de m o gra p hic a n d baseli ne c haracteristics for all  e nr olle d patient s will 
be ta b ulate d. Patie nts will be ta b ulate d b y c o h ort a n d o verall.
8. 3. 2
S afety A n alyses
S af et y will be assesse d b y cli nical re vie w of all rele va nt para m eters i nclu di n g A Es, S A Es, 
T E A E s, lab orat or y  val ues, vital si g ns, E C G res ults, a n d c o nc o mita nt me dicati o ns. U nless 
s pecifie d ot her wise, t he safety a nal yses will be c o n d ucte d f or t he safet y p o p ulat i on defi ne d i n
Secti o n 8. 1 . A baseli ne meas ure me nt a n d at least 1 la b orat or y  or ot her safety- relate d 
meas ure me nt o btai ne d after t he start of st u d y  dr u g ma y be re q uir e d for i ncl usi o n i n t he a nal ysis 
of  a s pecific safety para meter . Ta b ulat i ons will be pr o vi de d b y c o h ort a n d o verall.
I n vesti gat or will re p ort a ver bati m A E ter m . T he re p orte d A E ter m will be assi g ne d a 
sta n dar dize d preferre d ter m usi n g Me d D R A. T he in vesti gat or will gra de t he se verit y of  eac h A E 
C CI
C CI

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using, when applicable, the NCI CTCAE v5.0.  In the event of an AE for which no grading scale 
exists, the investigator will classify the AE as mild, moderate, severe, 
life-threatening/debilitating, or fatal.
Safety analyses will include summaries of the following: 

adverse events, including severity and possible relationship to study treatment

serious adverse events, including possible relationship to study treatment

adverse events leading to dose adjustments, treatment discontinuation, or death

discontinuations from study treatment or death
8.3.3
Efficacy Analyses
The primary analysis of efficacy will be based on the PAS. These analyses will be summarized 
by the specific B-cell malignancy (MCL and CLL/SLL).
ORR will be assessed using Lugano criteria (Appendix A) or IWCLL (Appendix B) including 
assessment of complete response with incomplete marrow recovery (CRi), nodular PR (nPR), 
and PR with lymphocytosis (PR-L), or IWWM (Appendix C), as appropriate to tumor type. The 
estimate of the ORR will be calculated as the proportion of patients with best overall response 
(BOR) of PR or better, based on IWCLL, PR or better based on Lugano, and minor response or 
better for WM based on IWWM criteria as determined by IRC and by the treating investigator. 
The estimates of the ORR will be accompanied by a 2-sided 95% CI. Waterfall plots will be 
used to depict graphically the maximum decrease from baseline in the sum of product diameters 
(SPD) of target lesions.
DOR will be calculated for patients who achieve a response of PR or better (minor response or 
better for WM). For such patients, DOR is defined as the number of months from the start date 
of the first documented response to the earlier of the documentation of definitive disease 
progression or death from any cause. Patients who are alive and without documented PD as of 
data analysis cutoff date will be censored. Details of the censoring rules will be provided in
SAP.
PFS will be derived for each patient as the number of months from the date of the first dose of 
study drug to the earlier of documented PD or death due to any cause. Patients who are alive 
and without documented PD as of data analysis cutoff date will be censored. Details of the 
censoring rules will be provided in SAP.
OS will be derived for each patient as the number of months from the date of the first dose of 
study drug to the date of death, irrespective of cause. Patients who are alive or lost to follow-up
as of a data analysis cutoff date will be censored. The censoring date will be determined from 
the last date the patient was known to be alive or data analysis cutoff date, whichever occurs 
first. Details of the censoring rules will be provided in SAP.
DOR, PFS, and OS will be summarized descriptively using the Kaplan-Meier method. 
Patients enrolled in Cohort 3 will be evaluated for efficacy in an exploratory manner separately 
from the primary efficacy analysis for Cohorts 1 and 2, but they will be included in the overall 
safety analysis.

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The association of clinical response categories (BOR) with changes in cancer-related symptoms 
(using EORTC symptom assessments) and physical function (using the EORTC-QLQ-C30 
Physical Functioning Subscale) for patients with MCL, CLL/SLL and other NHL tumors will be 
assessed.
8.3.4
Pharmacokinetic Analyses
Plasma concentrations of LOXO-305 will be determined with a validated bioanalytical assay. 
The following PK parameters will be calculated from plasma concentrations determined on the
patients as illustrated in Section 7.2. If appropriate: Cmax, Tmax, area under the concentration 
versus time curve from time 0 to t (AUC0–t), apparent oral clearance (CL/F), apparent volume of 
distribution (Vz/F), and T1/2.
Summary statistics will be generated by cohort and across cohorts as appropriate.
8.3.5
Primary Analysis
The main data cutting-off and primary analysis will be performed after all enrolled patients have 
been followed up for sufficient amount of time (6 months).  However, the primary analysis may 
be provided or updated upon request from regulatory authorities at any time during the study.

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9.
A D V E R S E E V E N T S
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of pat ient s w h o ha ve e ntere d t his st u d y 
a n d f or alerti n g Lill y or its desi g nee t o a n y e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y be 
c o nsi dere d a n u na nt ici pate d be nefit t o t he patie nts .   T he i n vest i gat or is res p o nsi ble f or t he 
a p pr o priate me dical care of pat ient s d uri n g t he st u d y . I n vesti gat ors m ust d oc u me nt t heir re vie w 
of  eac h la b orat or y safety re p ort.
T he i n vest i gat or re mai ns res p o nsi ble f or f oll owi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us or ot her wise me dicall y i m p orta nt, c o nsi dere d relate d t o t he i n vest i gati onal 
pr o d uct or t he st u d y , or t hat ca use d t he pati e nt t o disc o nti n ue t he i n vest i gati onal pr o d uct bef ore 
c o mplet i n g t he st u d y.  T he pati e nt s h o uld be f ol l owe d u nt il t he e ve nt res ol ves, sta bilizes wit h 
a p pr o priate dia g n ostic e val uati o n, or is reas o na bl y e x plai ne d.  T he fre q ue nc y o f f oll ow- u p 
e val uat i ons of t he A E is left t o t he discret i on of t he i n vest i gat or.  Lac k of dr u g effect is n ot a n 
A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y  is t o esta blis h treat me nt effect.
T he i n vest i gat or will rec or d all rele va nt A E a n d S A E i nf or mati on i n t he case re p ort f or m (C R F) .  
After t he I C F is si g ne d, st u d y  site pers o n nel will rec or d via C R F t he occ urre nce a n d nat ure of 
eac h pati e nt ’s pree xist i n g c o n diti ons, i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of t he 
di sease u n der treat me nt i n t he st u d y.  I n a d ditio n, si t e pers o n nel will rec or d a n y  c ha n ge i n t he 
c o n ditio n(s) a n d a n y  ne w c o n ditio ns as A Es.  I n vestigat ors s h o ul d rec or d t hei r assess me nt of t he 
p ote nti al relate d ness of eac h A E t o pr ot oc ol pr oce d ure, i n vesti gati onal pr o d uct, via C R F . T he 
i n vesti gat or s h o ul d pr o vi de A E ver bati m ter ms a n d t he n t he ter ms will be ma p pe d b y Lill y or its 
desi g nee t o c orres p o n di n g ter mi n o l og y  wit hi n t he Me d D R A L o wer le vel ter m dicti onar y. T he 
i n vesti gat or will use N CI C T C A E v 5. 0 t o assi g n A E se verity gra des.
T he i n vest i gat or will i nter pret a n d d oc u me nt w het her or n ot a n A E has a reas o na ble p ossi bility 
of  bei n g relate d t o st u d y treat me nt, or a st u d y pr oce d ure, ta ki n g i nt o acc o u nt t he disease, 
c o nc o mita nt treat me nt or pat h ol o gies.  A “reas o na ble p ossi bilit y” mea ns t hat t here is a ca use 
a n d effect relat i ons hi p bet wee n t he i n vesti gati o nal pr o d uct, a n d/ or st u d y  pr oce d ure a n d t he A E.  
T he i n vest i gat or a ns wers yes/ n o w he n ma ki n g t his assess me nt. Disease pr o gressi o n of t he 
pri mar y  t u mor i n a n d of itself is ca pt ure d as a n efficac y  assess me nt a n d s h o uld n ot be ca pt ure d 
as a n A E (incl u di n g fatal  A Es) u nless t he disease pr o gressi o n is assesse d as relate d t o st ud y 
treat me nt.  If t o xicities d ue t o P D e xist a n d are ne w or w orse ne d fr o m baseli ne, t hese s h o ul d be 
re p orte d as A Es.  If a ne w pri mar y mali g na nc y a p pears, it will als o be c o nsi dere d a n A E .
If a patie nt ’s i n vesti gati o nal pr o d uct is disc o nti n ue d as a res ult of  a n A E, st u d y site pers o n nel 
m ust re p ort t his t o Lill y or its desi g nee via C R F, clarif yi n g if p ossi ble, t he circ u msta nces lea di n g 
t o a n y d osa ge mo dificat i ons, or disc o nt i n uati ons of treat me nt.
Beca use of t he well d oc u me nte d l y m p h oc y t osis t hat occ urs earl y with a p pr o ve d B T K i n hi bit ors 
a n d is n ot ass ociate d wit h P D, pr o gressi ve l y m p h oc y t osis o n L O X O-3 0 5 i n t he a bse nce of ot her 
sig ns of  P D (e. g., s ple n o me gal y, e nlar gi n g l y m p h n o des, disease -relate d c o nstitut i onal 
s y m pt o ms) will n ot be c o nsi dere d P D.
9. 1
Seri o us A d verse E ve nt Re p orti n g
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n o ne of t he f oll owi n g o utc o m es:

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
Death

Initial or prolonged inpatient hospitalization

A life-threatening experience (that is, immediate risk of dying)

Persistent or significant disability/incapacity

Congenital anomaly/birth defect

Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. However, if institutional guidelines mandate hospitalization for a planned 
procedure (e.g., transfusion of blood products such as PRBCs, platelets or plasma), the 
underlying AE requiring intervention should not be reported as an SAE unless it meets other 
serious criteria.  An emergency room visit without hospital admission will not be recorded as an 
SAE under this criterion, nor will hospitalization for a procedure scheduled or planned before 
signing of the informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. Admission to the hospital for social or situational reasons (i.e., no place to stay, 
live too far away to come for hospital visits) will not be considered inpatient hospitalizations.
In the event of an accidental or intentional overdose by a patient, the site staff must immediately 
inform sponsor. The CRF must be updated to reflect this information. In the event that the 
overdose is associated with an SAE, the 2 events should be linked. In the event of an AE 
associated with an overdose, an SAE report form must be completed detailing the AE and the 
overdose details.
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product through 28 days after the last dose.  However, if an SAE occurs 
after signing the ICF, but prior to receiving investigational product, the SAE should be reported 
to the sponsor as per SAE reporting requirements and timelines if it is considered reasonably 
possibly related to study procedure. SAEs occurring after the SFU visit and judged by the 
investigator as related to study drug should be reported. Investigators are not obligated to 
actively seek AEs or SAEs in subjects once they have discontinued and/or completed the study 
(the patient disposition CRF has been completed).  However, if the investigator learns of any 
SAE, including a death, at any time after a subject has been discharged from the study, and 
he/she considers the event reasonably possibly related to the study treatment or study 
participation, the investigator must promptly notify Lilly.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-

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hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic adverse event should have additional data collected 
using the CRF (see Section 9.2).
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
Lilly has procedures that will be followed for the identification, recording and expedited 
reporting of SUSARs that are consistent with global regulations and the associated detailed 
guidance documents.
Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study patients, to monitor quality, and to facilitate 
process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.2
Hepatic Safety Monitoring
Close hepatic monitoring and evaluation.
If one or more of these following conditions occur:
If a patient with baseline results of
develops the following elevations:
ALT or AST <1.5x ULN
ALT or AST ≥5x ULN or
ALT or AST ≥3x ULN concurrent with TBL ≥2x ULN
ALT or AST ≥1.5x ULN
ALT or AST ≥3x baseline or
ALT or AST ≥2x baseline concurrent with TBL ≥2x ULN
liver testing should be repeated within 2 to 4 days including ALT, AST, ALP, TBL, direct 
bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the abnormality and to 
determine if a potential condition is improving or worsening.  If the abnormality persists or 
worsens, clinical and laboratory monitoring and evaluation for possible cause of abnormal liver 
tests (refer to Appendix N) should be initiated by the investigator in consultation with the study 
Lilly CRP. At a minimum, this evaluation should include physical examination and a thorough 
medical history, including symptoms, recent illnesses (for example, heart failure, systemic 
infection, hypotension, or seizures), history of concomitant medications (including over-the-
counter, herbal and dietary supplements, history of alcohol drinking and other substance abuse).
Monitoring of ALT, AST, TBL, and ALP should continue until levels normalize or return to 
approximate baseline levels. Dose modification should follow that outlined in Section 6.2.2.  
In addition, the evaluation should include a blood test for prothrombin time (PT-INR); 
serological tests for viral hepatitis A, B, C, E, autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or CT scan).  Based on the patient’s history and initial evaluation 
results, further testing should be considered in consultation with the Lilly designated medical 
monitor, including tests for hepatitis D virus (HDV), CMV, Epstein-Barr virus (EBV), 
acetaminophen levels, acetaminophen protein adducts, urine toxicology screen, Wilson’s 

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disease, blood alcohol levels, urinary ethyl glucuronide, and serum phosphatidylethanol.  Based 
on the circumstances and the investigator’s assessment of the patient’s clinical condition, the 
investigator should consider referring the patient for a hepatologist or gastroenterologist 
consultation, magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde 
cholangiopancreatography (ERCP), cardiac echocardiogram, and/or a liver biopsy.
Hepatic Safety Data Collection
Additional safety data (also refer to Appendix N) should be collected via the CRF if one or more 
of the following conditions occur: 
In patients enrolled with baseline ALT or AST <1.5 x ULN

Elevation of serum ALT or AST to ≥5x ULN on 2 consecutive tests

The combination of elevated ALT or AST ≥3 x ULN and elevated TBL ≥2 x ULN
In patients enrolled with baseline ALT or AST ≥1.5 x ULN

Elevated ALT or AST ≥3 x baseline on 2 consecutive tests

The combination of elevated ALT or AST ≥2 x baseline and elevated TBL ≥2 x ULN
In all study patients 

Discontinuation from study treatment due to a hepatic event or abnormality of liver 
tests

Occurrence of a hepatic event considered to be a SAE
9.3
Serious Adverse Event Follow-up
For all SAEs occurring during the study, the investigator must submit follow-up reports to the 
sponsor regarding the status of the SAE and the patient’s subsequent course until the SAE has 
resolved, or until the condition stabilizes or is deemed chronic (in the case of persistent 
impairment), or the patient dies.
9.4
Pregnancy Reporting
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
A patient becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination study procedures will be performed.
The patient or partner should be followed by the investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the investigator should notify 
sponsor. At the completion of the pregnancy, the investigator will document the outcome of the 
pregnancy. 

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10. STUDY ADMINISTRATION
10.1 Regulatory and Ethical Considerations
10.1.1
Regulatory Authority Approval
This study will be conducted in accordance with the standard of International Council for 
Harmonisation-Good Clinical Practice (ICH GCP), an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that involve human patients.
Compliance with these standards provides assurance that the rights, safety, and well-being of 
study patients are protected, consistent with the principles in the Declaration of Helsinki, and 
that the clinical study data are credible.
10.1.2
Ethics Approval
It is the responsibility of the investigator to ensure that the appropriate Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) has reviewed and approved this protocol 
prior to initiating the study. The investigator must provide the sponsor or sponsor’s 
representative with current and revised IRB/IEC membership rosters that include the members’ 
occupations and qualifications. 
The IRB/IEC must also review and approve the clinical site’s ICF, other written information
provided to the patient, and all advertisements that may be used for patient recruitment. The 
investigator will provide the study monitor with copies of these documents and of dated 
IRB/IEC approval(s) prior to the start of the study.
If the protocol or the ICF is amended during the study, the investigator is responsible for 
ensuring that the IRB/IEC has reviewed and approved these amended documents. Approval of 
the amended documents must be obtained from the IRB/IEC before implementation and before 
new patients are consented to participate in the study using the amended version of the ICF. 
The investigator must provide the sponsor with the dated IRB/IEC approval of the amended 
documents as soon as available.
10.1.3
Patient Informed Consent
Prior to study entry, the investigator or designee will explain the nature, purpose, benefits, and 
risks of participation in the study to each patient, patient’s legally acceptable representative, or 
impartial witness. Written informed consent must be obtained prior to the patient entering the 
study (before initiation of any study-related screening procedure).  Sufficient time will be 
allowed to discuss any questions raised by the patient. The ICF must be signed by all patients.  
The process of obtaining consent will be in compliance with all applicable regulations and ICH 
requirements.
If the ICF is amended during the study, the investigator must follow all applicable regulatory 
requirements pertaining to IRB/IEC approval of the amended form. The clinical site must use 
the amended ICF for all new patients and must re-consent any ongoing patients with the 
amended ICF, if instructed to do so by the IRB/IEC.

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The sample ICF prepared by the sponsor is provided in the Study Manual. The consent and re-
consenting process should be properly documented in the source documentation.
10.1.4
Serious Adverse Event Notification to the Institutional Review Board/Independent 
Ethics Committee
SUSARs will be reported to the IRB/IEC according to their institutional policy by the 
investigator or sponsor (or sponsor designee) according to country requirements. Copies of each 
report and documentation of IRB/IEC notification and acknowledgement of receipt will be kept 
in the investigator’s study file.
10.1.5
Sponsor Safety Reporting to Regulatory Authorities
The sponsor or its representative is required to report certain study events in an expedited 
manner to the Regulatory Authorities according to local applicable regulations.
The following describes the safety reporting timeline requirements for SUSARs and other 
reportable events:
Immediately and within 7 calendar days:

Any suspected AE that is associated with the use of the study drug, unexpected, and 
fatal or life-threatening. Follow-up information must be reported in the following 8
days.
Immediately and within 15 calendar days:

Any suspected AE that is associated with the use of the study drug, unexpected, and 
serious, but not fatal or life-threatening, and there is evidence to suggest a causal 
relationship between the study drug and the event.

Any finding from tests in laboratory animals that suggest a significant risk for human 
patients, including reports of mutagenicity, teratogenicity, or carcinogenicity.

Any event in connection with the conduct of the study or the development of the 
study drug that may affect the safety of the study patients. In addition, periodic 
safety reporting to regulatory authorities will be performed by the sponsor or its 
representative according to national and local regulations.

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 7 9
L Y 3 5 2 7 7 2 7
1 0. 2
D at a M a n a ge me nt
S o urce d oc u me nts will be mai ntai ne d b y sites a n d use d t o e nter data a n d c o m plete t he C R F s i n 
t he cli nical data base ( electr o nic data ca pt ure [E D C ]) . T he sp o ns or’s m o nit ors will r o uti nel y  
re vie w t he s o urce d oc u me ntati o n a n d verif y t he c orres p o n di n g data e ntere d o n C R F s i n t he 
cli nical data base. All e ntere d, c ha n ge d, a n d fi nal data s hall be a vaila ble wit h a vali date d a u dit 
trail re p ort or data e xtract re p ort. T he C R F s s hall be c o nsi dere d c o m plete w he n all e x pecte d 
data has bee n e ntere d a n d all discre pa ncies ha ve bee n res o l ve d or d oc u me nte d.
T he in vest i gat or m ust si g n all C R F s acc or di n g t o t he E D C re q uire me nts.
1 0. 3
St u d y M o nit ori n g
Pri or t o t he start of t he st u d y , t he sp o ns or’s m o ni t or will c o ntact t he cli nical site t o disc uss t he 
pr ot oc ol  a n d data c ollecti on pr oce d ures a n d c o n d uct a p plica ble trai ni n g of site pers o n nel. T he 
sp o ns or a n d i ts desig nees will als o peri o dicall y c o ntact t he cli nical site d uri n g t he c o n d uct of t he 
st u d y ( w hic h will incl u de o n -site visits) i n acc or da nce with a p plica ble re g ulat i ons a n d G C P. 
D uri n g t hese c o ntacts, t he m o nit ori n g act i vities will i ncl u de:

C hec ki n g a n d assessi n g t he pr o gress of t he st u d y

Re vie wi n g st u d y  data c ollecte d t o date f or c o mplete ness a n d acc urac y

C o n d ucti n g s o urce d oc u me nt verificat i ons b y re vie wi n g eac h pat ient ’s C R F a gai nst 
s o urce d oc u me nts

I de ntif yi n g a n y iss ues a n d a d dressi n g res ol uti ons

Rec or di n g a n d re p orti n g pr ot oc ol de viat i ons n ot pre vi o usl y re p orte d t o t he sp o ns or

C o nfir mi n g t hat S A Es ha ve bee n pr o perl y re p orte d t o t he s p o ns or a n d s u b mitte d t o 
t he I R B/I E C, if a p pr o priate.
T hese act i vities will be d o ne i n or der t o verif y t hat t he data are a ut he ntic, acc urate, a n d
c o mplete; t hat t he safet y a n d rig hts of  t he patient  are bei n g pr otecte d; a n d t hat t he st u d y is 
c o n d ucte d i n acc or da nce wit h t he c urre nt l y a p pr o ve d pr ot oc ol, I C H G C P, a n d all a p plica ble 
re g ulat or y r e q uire me nts. A d dit i onall y, t o e ns ure c o m plia nce wit h I C H G C P a n d all a p plica ble 
re g ulat or y r e q uire me nts, t he sp o ns or or desi g nee ma y c o n d uct a q ualit y ass ura nce a u dit.
1 0. 4
Ter mi n ati o n
U p o n c o m plet i on of t he st u d y , t he f oll owi n g act i vities, w he n a p plica ble, m ust be c o n d ucte d b y 
t he sit e mo ni t or a n d t he in vest i gat or:

S u b missi o n o f all st u d y data t o t he sp o ns or

C o m plet i on of all data clarificati o ns a n d/ or res ol uti o ns

Rec o nciliat i on a n d fi nal dis p osit i on of i n vest i gati onal pr o d uct

Re vie w of site st u d y  files f or c o mplete ness

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In addition, the sponsor reserves the right to temporarily suspend or prematurely terminate this 
study for any reason.
If the study is suspended or terminated for safety reasons, the sponsor will promptly inform the 
investigator and will also inform the IRB/IEC with the reasons for the action. In the event of 
prematurely termination, all study data must be submitted to the sponsor. In addition, the 
clinical site must document final disposition of all unused investigational product in accordance 
with the sponsor’s procedures.
10.5 Records Retention
Patient records, source documents, monitoring visit logs, investigational product inventory, 
regulatory documents, and other correspondence pertaining to the study must be maintained in 
the appropriate site study files according to ICH GCP and applicable regulatory requirement(s). 
These records will be retained for the period required by the institution or site policy. Prior to 
transfer or destruction of these records, the sponsor must be notified in writing.
10.6 Confidentiality of Information
Patient names will remain confidential and will not be supplied to the sponsor or its designee. 
The investigator will maintain a personal patient identification list (patient and treatment 
numbers with the corresponding patient names) to enable records to be identified.

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11. APPENDICES

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Appendix A
Lugano Classification of Response in Non-Hodgkin Lymphoma
Table 11.1
Lugano Classification of Response
Response and Site
PET-CT–Based Response
CT-Based Response
Complete a
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and extra 
lymphatic sites
Score 1, 2, or 3* with or without a residual mass on 5PS†
It is recognized that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum and/or 
liver. In this circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high physiologic 
uptake
Target nodes/nodal masses must regress to ≤1.5 cm in LDi
No extralymphatic sites of disease
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following):
Lymph nodes and 
extralymphatic sites
Score 4 or 5† with reduced uptake compared with baseline and 
residual mass(es) of any size
At interim, these findings suggest responding disease
At end of treatment, these findings indicate residual disease
≥50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites
When a lesion is too small to measure on CT, assign 5 mm × 5 mm 
as the default value
When no longer visible, 0 × 0 mm
For a node >5 mm × 5 mm, but smaller than normal, use actual 
measurement for calculation
Nonmeasured lesions 
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length beyond normal

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Response and Site
PET-CT–Based Response
CT-Based Response
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow, but
reduced compared with baseline (diffuse uptake compatible with 
reactive changes from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the context of a nodal 
response, consideration should be given to further evaluation with 
MRI or biopsy or an interval scan
Not applicable
No response or stable 
disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment
<50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 1 of the following PPD 
i
Individual target 
nodes/nodal masses 
Extranodal lesions
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be abnormal with: LDi >1.5 cm 
and
Increase by ≥50% from PPD nadir and an increase in LDi or SDi 
from nadir
0.5 cm for lesions ≤2 cm
1.0 cm for lesions >2 cm
In the setting of splenomegaly, the splenic length must increase 
by >50% of the extent of its prior increase beyond baseline 
(e.g., a 15-cm spleen must increase to
>16 cm). If no prior splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
Nonmeasured lesions
None
New or clear progression of preexisting nonmeasured lesions

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Response and Site
PET-CT–Based Response
CT-Based Response
New lesions
New FDG-avid foci consistent with lymphoma rather than another 
etiology (e.g., infection, inflammation). If uncertain regarding 
etiology of new lesions, biopsy or interval scan may be considered
Regrowth of previously resolved lesions
A new node >1.5 cm in any axis
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
Abbreviations:  5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; GI = gastrointestinal; IHC = immunohistochemistry; LDi = longest 
transverse diameter of a lesion; MRI = magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular 
diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the product of the perpendicular diameters for multiple lesions.
a.
For MCL in Cohort 1, bone marrow biopsy and aspiration, esophagogastroduodenoscopy (EDG) and colonoscopy with random segmental biopsies (for 
patients with known or evidence of GI involvement at baseline) must be performed to confirm radiographic CR.
*
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving 
PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment).
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes 
should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation.
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability, but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging.
In Waldeyer’s ring or in extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic 
response, but should be no higher than surrounding normal physiologic uptake (e.g., with marrow activation as a result of chemotherapy or myeloid growth 
factors).
†
PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum, but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
For complete Lugano Classification, please refer to: Cheson et al. 2014.

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Appendix B
Chronic Lymphocytic Leukemia Response Assessment (IWCLL)
Table 11.2
Response Definition after Treatment of CLL/SLL Patients
Group
Parameter
CR
PR
PD
SD
A
Lymph nodes
None ≥ 1.5 cm
Decrease ≥ 50% 
(from baseline)a
Increase ≥50% 
from baseline or 
from response
Change of -49%
to +49%
Lymph and/or 
spleen sizeb
Spleen size 
<13 cm; liver 
size normal
Decrease ≥50% 
(from baseline)
Increase ≥50% 
from baseline or 
from response
Change of -49%
to +49%
Constitutional 
symptoms
None
Any
Any
Any
Circulating 
lymphocyte 
count
Normal
Decrease ≥50% 
from baseline
Increase ≥50% 
over baseline
Change of -49%
to +49%
B
Platelet count
≥100 × 109/L
≥100 × 109/L or 
increase ≥50% 
over baseline
Decrease of ≥50% 
from baseline 
secondary to 
Change of -49%
to +49%
Hemoglobin
≥11.0 g/dL
(untransfused
and without
erythropoietin)
≥11.0 g/dL or
increase ≥50%
over baseline
Decrease of
≥2 g/dL from
baseline secondary
to CLL/SLL
Increase
<11.0 g/dL or
<50% over
baseline, or
decrease <2 g/dL
Marrow
Normo-cellular,
no CLL/SLL 
cells, no
B-lymphoid
nodules
Presence of 
CLL/SLL
cells, or of B-
lymphoid nodules,
or not done
Increase of 
CLL/SLL
cells by ≥50% on
successive
biopsies
No change in
marrow infiltrate
Abbreviations: CLL = chronic lymphocytic leukemia; CR = complete remission (all of the criteria have to be 
met); PD = progressive disease (at least 1 of the criteria of group A or group B has to be met); PR = partial remission 
(for a PR, at least 2 of the parameters of group A and 1 parameter of group B need to improve if previously 
abnormal; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 needs to improve); SD =
stable disease (all of the criteria have to be met; constitutional symptoms alone do not define PD); SLL = small 
lymphocytic lymphoma.
a
Sum of the products of 6 or fewer lymph nodes (as evaluated by CT scans and physical examination in clinical 
trials or by physical examination in general practice).
b
Spleen size is considered normal if < 13 cm. There is not firmly established international consensus of the size 
of a normal liver; therefore, liver size should be evaluated by imaging and manual palpation in clinical trials 
and be recorded according to the definition used in a study protocol.
For complete IWCLL guideline, please refer to Hallek et al. 2018.
In addition to the CR, PR, PD and SD response definition as listed in the table above, the 
protocol requires response assessments of complete response with an incomplete marrow 
recovery (CRi), nodular Partial Response (nPR), and PR with lymphocytosis (PR-L), as 
explained below:

In assessing response, PR-L, which is defined as only 1 abnormal Group A criteria met in 
the setting of lymphocytosis not meeting PR criteria, may also be summarized for patients 
with CLL/SLL so as to not underestimate overall response in the setting of BTK inhibitor 
therapy (Cheson et al. 2012).

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
For CRi response, patients must fulfill all criteria for a CR with persistent anemia, 
neutropenia and thrombocytopenia and investigator must attribute these cytopenias as 
related to investigational drug and not due to the underlying disease.

For nPR, patients must fulfill all criteria for a CR, but the bone marrow biopsy/aspirate 
shows B-lymphoid nodules which are evidence for residual disease.
Isolated new lymphocytosis initially occurring during Cycle 1 will not be used as criteria for 
determining PD.

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Appendix C
Waldenström Macroglobulinemia Response Assessment (IWWM)
Table 11.3
Waldenström Macroglobulinemia Response Assessment Criteria
Response Category
Description
CR
Absence of serum monoclonal IgM protein by immunofixation
Normal serum IgM level
Complete resolution of extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline
Morphologically normal bone marrow aspirate and trephine biopsy
VGPR
Monoclonal IgM protein is detectable
≥90% reduction in serum IgM level from baselinea
Complete resolution of extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline
No new signs or symptoms of active disease
PR
Monoclonal IgM protein is detectable
≥50% but < 90% reduction in serum IgM level from baselinea
Reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly 
if present at baseline
No new signs or symptoms of active disease
MR
Monoclonal IgM protein is detectable
≥25% but < 50% reduction in serum IgM level from baselinea
No new signs or symptoms of active disease
SD
Monoclonal IgM protein is detectable
< 25% reduction and < 25% increase in serum IgM level from baselinea
No progression in extramedullary disease, i.e., 
lymphadenopathy/splenomegaly if present at baseline
No new signs or symptoms of active disease
PD
≥25% increase in serum IgM levela,b from lowest nadir (requires 
confirmation) and/or progression in clinical features attributable to the 
disease
Abbreviations:  CR = complete remission; MR = minor response; PD = progressive disease; PR = partial remission; 
SD = stable disease; VGPR = very good partial response.
a
Sequential changes in IgM levels may be determined by either M-protein quantitation by densitometry or 
total serum IgM quantitation by nephelometry.
b
An absolute increase of >5 G/L (0.5 g/dL) is required when the increase of IgM component is the only 
applicable criterion.
For complete IWWM guideline, please refer to:  Anderson, J Natl Compr Canc Netw. 2012; 10(10):1211-1219.

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Appendix D
Treatment Failure and Intolerance
Treatment Failure:
Relapse:  evidence of disease progression according to disease-defined criteria in a patient who 
has previously achieved a complete response (CR) or partial response (PR) for ≥6 months (WM 
patients with an IWWM defined minor response for ≥6 months would also be considered as 
relapsed at time of disease progression).
Refractory disease:  treatment failure as defined by less than CR or PR (i.e., stable disease [SD], 
nonresponse, progressive disease [PD]) or progression within 6 months from the last dose of 
therapy.
Treatment Intolerance:

≥1 Grade 3 or ≥2 Grade 2 non-hematologic toxicities or

≥1 Grade 3 neutropenia with infection or fever or

≥1 Grade 4 hematologic toxicity

The above leads to treatment discontinuation for ≥14 days without disease 
progression (patient could have progressed after 14 days)

Toxicities should resolve to ≤ Grade 1 off therapy
References:
(Hallek et al. 2018, Mato 2018)

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Appendix E
Prior BTK Inhibitors
This list represents the names of known BTK inhibitors.  If a patient has been on a BTK 
inhibitor that is not represented on this list, the sponsor should be contacted for a discussion 
regarding the prior BTK inhibitor to ensure appropriate cohort assignment at patient enrollment.
Prior BTK inhibitors used in the treatment of CLL/SLL or NHL include, but are not limited to:

Acalabrutinib

DTRMWXHS-12

GDC-0853

Ibrutinib

Orelabrutinib (ICP-022)

SHR1459

TG-1701

Zanubrutinib (BGB-3111)

Evobrutinib (M7583)

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 9 0
L Y 3 5 2 7 7 2 7
A p pe n di x F
I n dic ati o n f or Tre at me nt of C L L/ S L L
F or treat m e nt i nit iati on, at least 1 of t he f o ll owi n g cri teria s h o uld be met :
1.
E vi de nce of pr o gressi ve marr o w fail ure as ma nifeste d b y t he de vel o p me nt of, or w orse ni n g 
of , a ne mia a n d/ or t hr o m b oc yt o p e nia. C ut off le vels of  H b < 1 0 g/ d L or platelet c o u nts
< 1 0 0 ×
1 0 9/ L are ge nerall y re gar de d as i n dicati on f or treat me nt. H o we ver, i n s o me 
pati e nts, platelet c o u nts < 1 0 0 ×
1 0 9/ L ma y re mai n sta ble o ver a l o n g peri o d; t his sit uati on
d oes n ot a ut o maticall y  r e q uire t hera pe utic i nt er ve ntio n.
2.
Massi ve (i . e., ≥6 c m bel o w t he left c ostal mar gi n) or pr o gressi ve or s y m pt o matic 
s ple n o me gal y.
3.
Massi ve n o des (i . e., ≥1 0 c m i n l o n gest di a meter) or pr o gressi ve or s y m pt o matic 
l y m p ha de n o pat h y.
4.
Pr o gressi ve l y m p h oc y t osis wit h a n i ncrease of ≥5 0 % o ve r a 2- m o nt h p eri o d, or l y m p h oc y t e
d o u bli n g ti me ( L D T) < 6 m o nt hs.   L D T ca n be o btai ne d b y li near re gressi o n e xtra p olat i on of
a bs o l ute l y m p h oc yte c o u nts o btai ne d at i nter vals of 2 wee ks o ver a n o bser vati o n peri o d of 
2 t o 3 mo nt hs; pat ient s wit h i nitial bl o o d l y m p h oc yte c o u nts < 3 0 ×
1 0 9/ L ma y re q uire a
l on ger o bser vati o n peri o d t o deter mi ne t he L D T. Fact ors c o ntri b ut i n g t o l y m p h oc yt osis 
ot her t ha n C L L (e . g., infect i ons, ster oid a d mi nistrati o n) s h o ul d be e xcl u de d.
5.
A ut oi m m u ne c o m plicati o ns i ncl u di n g a ne mia or t hr o m b oc y t o p e nia p o orl y  res p o nsi ve t o 
c ortic oster oids.
6.
S y m pt o m atic or f u nct i onal e xtra n o dal i n v o l ve me nt (e.g. , s ki n, ki d ne y , l u n g, s pi ne).
7.
Di sease-relate d s y m pt o ms as defi ne d b y a n y of t h e fol l owi n g:
a.
U ni nte nt i onal wei g ht l oss ≥1 0 % wi t hi n t he pre vi ous 6 m o nt hs.
b.
Si g nifica nt fati g ue (i . e., E C O G perf or ma nce scale 2 or w orse; ca n n ot w or k or u na ble t o 
perf or m  us ual acti vities).
c.
Fe vers ≥3 8. 0° C f or 2 or m ore wee ks wi t ho ut e vi de nce o f i nfecti on.
d.
Ni g ht s weats f or ≥1 m o nt h wi t ho ut e vi de nce of i nfecti o n.

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Appendix G
New York Heart Association (NYHA) Functional Classification
Table 11.4
Classes of Heart Failure
Class
Patient Symptoms
Class
Objective Assessment
Ⅰ
No limitation of physical activity. Ordinary 
physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of 
breath).
A
No objective evidence of cardiovascular 
disease. No symptoms and no limitation in 
ordinary physical activity.
Ⅱ
Slight limitation of physical activity. 
Comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, 
dyspnea (shortness of breath).
B
Objective evidence of minimal cardiovascular 
disease. Mild symptoms and slight limitation 
during ordinary activity. Comfortable at rest.
Ⅲ
Marked limitation of physical activity. 
Comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, or 
dyspnea.
C
Objective evidence of moderately severe 
cardiovascular disease. Marked limitation in 
activity due to symptoms, even during less-
than-ordinary activity. Comfortable only at 
rest.
Ⅳ
Unable to carry on any physical activity 
without discomfort. Symptoms of heart 
failure at rest. If any physical activity is 
undertaken, discomfort increases.
D
Objective evidence of severe cardiovascular 
disease. Severe limitations. Experiences 
symptoms even while at rest.

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Appendix H
Examples of Agents Known to Cause QTc Prolongation
Table 11.5
Examples of Agents Known to Cause QTc Prolongation
Examples of Agents Known to Cause QTc Prolongation
amiodarone
ibogaine 
anagrelide
ibutilide
azithromycin
levofloxacin
chloroquine
levomepromazine (methotrimeprazine) 
chlorpromazine
levosulpiride 
cilostazol
methadone
ciprofloxacin
moxifloxacin
citalopram
ondansetron
clarithromycin
papaverine HCl (intracoronary)
cocaine
pentamidine
disopyramide
pimozide
dofetilide
procainamide
domperidone 
propofol
donepezil
quinidine
dronedarone
roxithromycin 
droperidol
sevoflurane
erythromycin
sotalol
escitalopram
sulpiride 
flecainide
sultopride 
fluconazole
terlipressin 
halofantrine 
terodiline 
haloperidol
thioridazine
hydroquinidine, dihydroquinidine 
Note: The above list is not exhaustive. Please refer to www.crediblemedicines.com for a current list of agents known 
to cause QTc prolongation, as well as agents with a possible or conditional risk.

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Appendix I
Inhibitors and Inducers of CYP3A4
Table 11.6
Inhibitors of CYP3A4
Strong inhibitors a
Moderate inhibitors b
boceprevir
amprenavir
clarithromycin
aprepitant
cobicistat
atazanavir (see atazanavir and ritonavir)
conivaptan
atazanavir and ritonavir
danoprevir and ritonavir
cimetidine
diltiazem
ciprofloxacin
elvitegravir and ritonavir
clotrimazole
grapefruit juice
crizotinib
idelalisib
cyclosporine
indinavir and ritonavir
darunavir
itraconazole
dronedarone
ketoconazole
duvelisib
lopinavir and ritonavir
erythromycin
nefazodone
fedratinib
nelfinavir
fluconazole
posaconazole
fluvoxamine
ribociclib
fosnetupitant and palonosetron (see also netupitant)
ritonavir
imatinib
saquinavir and ritonavir
indinavir (see indinavir and ritonavir)
telithromycin
isavuconazole
tipranavir and ritonavir
ledipasvir/sofosbuvir
Viekira Pak (paritaprevir and ritonavir and 
ombitasvir and/or dasabuvir)
lefamulin
voriconazole
letermovir
magnolia vine (Schisandra sphenanthera)
netupitant
nilotinib
tofisopam
verapamil
voxelotor
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4.
a
Increases the AUC of the substrate by ≥5-fold.
b
Increases the AUC of the substrate by 2- to 5-fold.

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Table 11.7
Inducers of CYP3A4
Strong inducers a
Moderate inducers b
aminoglutethimide
almorexant
apalutamide
bosentan
avasimibe
cenobamate
carbamazepine
dabrafenib 
enzalutamide
daclatasvir and asunaprevir and beclabu
fosphenytoin
danshen (Salvia miltiorrhiza) 
ivosidenib
efavirenz
lumacaftor
encorafenib
mitotane
etravirine
phenobarbital
faldaprevir and efavirenz
phenytoin
genistein
rifabutin
lersivirine
rifampicin (rifampin)
lesinurad
rifapentine
lopinavir (alone)
St John’s wort
lorlatinib
modafinil
nafcillin (intravenous)
pentobarbital
primidone
telotristat ethyl
thioridizine
tipranavir and ritonavir
tocilizumab (atlizumab)
Abbreviations: AUC = area under the concentration versus time curve; CYP3A4 = cytochrome P450 3A4.
a
Decreases the AUC of the substrate by ≥80%.
b
Decreases the AUC of the substrate by 50% to 80%.
Note: The above lists are not exhaustive. Also refer to: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions.

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Appendix J
P-gp inhibitors
Given that LOXO-305 is a substrate of P-gp, inhibitors of P-gp could adversely affect the 
metabolism of LOXO-305. Therefore, the use of strong P-gp inhibitors is contraindicated while 
taking LOXO-305.
Table 11.8
Examples of Strong P-gp Inhibitors
Amiodarone
Clarithromycin
Cyclosporine
Diltiazem
Donedarone
Erythromycin
Felodipine
Fluconazole
Itraconazole
Ketoconazole
Lapatinib
Lopinavir
Propafenone
Ranolazine
Ritonavir
Telaprevir
Saquinavir
Quinidine
Verapamil
Note: The above list is not exhaustive. Also refer to: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions.

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Appendix K
Guidelines for Patient Sample Collection for Central Analysis
Selected patient samples from peripheral blood, bone marrow and/or nodal/extra-nodal sites will be collected during the conduct of this 
study for central assessment (except for PK). The following table is meant to be a guide; refer to the Laboratory Manual for additional
details.
Table 11.9
Guidelines for Patient Sample Collection for Central Analysis
Tumor Type
Time Point
Peripheral Blooda
Bone Marrowa
Lymph Node/Tumor 
Tissue
MCL
Baseline
Required unless available after last 
treatment or while progressing on the 
most recent treatment and performed
within 90 days
Required for patients 
enrolled in Cohort 1 for 
central pathology review
Response time points
Required to confirm CR if known disease 
involvement at baseline
Progression
Optional
CLL/SLL
Baseline
Required for response assessmentb 
Required unless available after last 
treatment or while progressing on the 
most recent treatment and performed 
within 90 days
Response time points Required for response assessmentb 
Required at CR
Progression
Required for response assessmentb 
Optional
WM
Baseline
Required for response assessmentb 
Required unless available after last 
treatment or while progressing on the 
most recent treatment and performed 
within 90 days
Response time points Required for response assessmentb 
Required at CR
Progression
Required for response assessmentb 
Optional

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Tumor Type
Time Point
Peripheral Blooda
Bone Marrowa
Lymph Node/Tumor 
Tissue
Indolent NHL 
(e.g., MZL, FL)c
Baseline
Required unless available after last 
treatment or while progressing on the 
most recent treatment and performed 
within 90 days
Response time points
Required to confirm CR if known disease 
involvement at baseline
Progression
Optional
Non-MCL High 
grade NHL (e.g., 
DLBCL)c
Baseline
May be required if unexplained cytopenia 
present at screening suggestive of bone 
marrow involvement unless available after 
last treatment or while progressing on the 
most recent treatment and performed within 
90 days.
Response time points
Required at CR only if known disease 
involvement at baseline, per Lugano staging 
criteria, positron emission tomography (PET) 
scan assessment of marrow response is 
acceptable a
Progression
Optional
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete remission; DLBCL = diffuse large b cell lymphoma; FL = Follicular lymphoma; MCL = mantle 
cell lymphoma; MZL = marginal zone lymphoma; NHL = non-Hodgkin lymphomas; SLL = small lymphocytic lymphoma; WM = Waldenström macroglobulinemia.
a
Sample collection for local tumor assessment is also needed. 
b
Laboratory studies for response assessment includes blood count with differential for CLL patients and SPEP/immunofixation/serum free light 
chains/quantitative immunoglobulins for WM patients.
c
According to Lugano staging criteria, PET scan can be used to assess bone marrow involvement and response in DLBCL.

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Appendix L
Eastern Cooperative Oncology Group Performance Scale Table
Table 11.10
Eastern Cooperative Oncology Group Performance Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead

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Appendix M Patient Reported Outcome (PRO) Assessments
EORTC QLQ-C30
Health-related quality of life will be assessed using the European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Core 30 Version 3.0 (EORTC QLQ-C30; 
Aaronson, et al. 1993). It is a copyrighted instrument, which has been translated and validated in 
over 100 languages and is used in more than 3,000 studies worldwide. This study utilizes
version 3.0, and the Study Manual should be consulted for instructions on implementing and 
scoring.
The EORTC QLQ-C30 consists of 30 total items within 3 dimensions:

Global health status/quality of life (2 items)

Functional scales (15 total items assessing physical, role, emotional, cognitive, or social 
functioning)

Symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, or financial impact).
Six of the 13 symptom items assessed by the EORTC QLQ-C30 are hypothesized to be 
associated with CLL/SLL: Dyspnea, Fatigue (3 items), General Pain, and Sleep Problems. 
Seven of the 13 are hypothesized to be associated with B-Cell NHL: Nausea, Dyspnea, Fatigue 
(3 items), General Pain, and Sleep Problems. These are supplemented by additional items from 
the EORTC Item Library: EORTC IL63 (for MCL).
Upon further exploration, a select number of these symptom items (in addition to those assessed 
by EORTC IL63) will be used to assess symptomatic response.
References:
EORTC website: http://groups.eortc.be/qol/eortc-qlq-c30 (Aaronson et al. 1993).
EORTC Symptom Assessments: EORTC IL63
In addition to the EORTC QLQ-C30, patients with MCL will complete a supplemental set of 
symptom items that are hypothesized to be associated with their respective malignancy:

Patients with MCL will complete the EORTC IL63, which consists of 6 additional symptom 
items: Night sweats, Fever/Chills, Fatigue (3 items), and Bloating of the abdomen.
Upon further exploration, a select number of these symptom items (in addition to those assessed 
by the EORTC QLQ-C30) will be used to assess symptomatic response.

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Appendix N
Liver Safety: Suggested Actions and Follow-Up Assessments
Table 11.11
Liver Evaluation Testing
Hepatic Evaluation Testing – Refer to protocol Hepatic Safety Monitoring Section 9.2 for guidance on 
appropriate test selection.

Results will be reported if a validated test or calculation is available.
Hematology
Clinical Chemistry
Hemoglobin
Total bilirubin
Hematocrit
Direct bilirubin
Erythrocytes (RBCs - Red Blood Cells)
Alkaline phosphatase (ALP)
Leukocytes (WBCs - White Blood Cells)
Alanine aminotransferase (ALT)
Differential:
Aspartate aminotransferase (AST)
    Neutrophils, segmented
Gamma-glutamyl transferase (GGT)
    Lymphocytes
Creatine kinase (CK)
    Monocytes
Other Chemistry
    Basophils
Acetaminophen
    Eosinophils
Acetaminophen Protein Adducts
Platelets
Alkaline Phosphatase Isoenzymes
Cell morphology (RBC and WBC)
Ceruloplasmin
Coagulation
Copper
Ethyl Alcohol (EtOH)
Prothrombin Time, international normalized ratio 
(PT-INR)
Haptoglobin
Serology
Immunoglobulin IgA (Quantitative)
Hepatitis A Virus (HAV) Testing:
Immunoglobulin IgG (Quantitative)
    HAV Total Antibody
Immunoglobulin IgM (Quantitative)
    HAV IgM Antibody
Phosphatidylethanol (PEth)
Hepatis B Virus (HBV) Testing:
Urine Chemistry
    Hepatitis B surface antigen (HBsAg)
Drug Screen
    Hepatitis B surface antibody (Anti-HBs)
Ethyl glucuronide (EtG)
    Hepatitis B core total antibody (Anti-HBc)
Other Serology
    Hepatitis B core IgM antibody
Anti-nuclear antibody (ANA)
    Hepatitis B core IgG antibody
Anti-smooth muscle antibody (ASMA) a
    HBV DNA c
Anti-actin antibody b
Hepatis C Virus (HCV) Testing:
Epstein-Barr Virus (EBV) Testing:
    HCV antibody
    EBV antibody

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    HCV RNA c
    EBV DNA c
Hepatitis D Virus (HDV) Testing:
Cytomegalovirus (CMV) Testing:
    HDV antibody
    CMV antibody
Hepatitis E Virus (HEV) Testing:
    CMV DNA c
    HEV IgG antibody
Herpes Simplex Virus (HSV) Testing:
    HEV IgM antibody
    HSV (Type 1 and 2) antibody
    HEV RNA c
    HSV (Type 1 and 2) DNA c
Microbiology 
Liver Kidney Microsomal Type 1 (LKM-1) Antibody
Culture:
    Blood
    Urine
a
Not required if anti-actin antibody is tested.
b
Not required if anti-smooth muscle antibody (ASMA) is tested.
c
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.

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Appendix O
Provisions for Changes in Study Conduct During Exceptional
Circumstances
Implementation of this appendix
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator.
Exceptional circumstances
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures.
Implementing changes under exceptional circumstances
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records.
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed.
Considerations for making a change
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study. 
Informed consent
Additional consent from the participant will be obtained, if required, for:

participation in remote visits, as defined in Section “Remote Visits,”

a change in the method of study intervention administration,  

dispensation of additional study intervention during an extended treatment period, 

alternate delivery of study intervention and ancillary supplies, and

provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances
Changes in study conduct not described in this appendix, or not consistent with applicable local 

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regulations, are not allowed.
The following changes in study conduct will not be considered protocol deviations.
Remote visits
Types of remote visits
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include but are 
not limited to concomitant medications.
Data capture
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits.
Safety reporting
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of adverse events (AEs), serious adverse events (SAEs), and product complaints 
remain unchanged. 
Return to on-site visits
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff.
Local laboratory testing option
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations.
Study intervention and ancillary supplies (including participant diaries)
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions.  These actions may 
include:  

asking the participant to go to the site and receive study supplies from site staff without 
completion of a full study visit, 

asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, 

arranging delivery of study supplies.
These requirements must be met before action is taken:

Alternate delivery of study intervention should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study supplies.

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
When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage conditions 
maintained and intact packaging upon receipt).

Instructions may be provided to the participant or designee on the final disposition of any 
unused or completed study supplies.
Screening period guidance
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening visit are valid for a maximum of 7 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances:

If screening is paused for less than 7 days from screening visits to randomization visit: 
the participant will proceed to the next study visit per the usual Schedule of Activities, 
provided that randomization visit must be conducted within 7 days from first screening 
visit. 
o
The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay.
o
Due to the pause in screening, sites should also reconfirm the impacted participant’s 
consent and document this confirmation in the source documentation.

If screening is paused for more than 7 days from screening visits to randomization visit: 
The participant must be discontinued because of screening interruption due to an 
exceptional circumstance. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the usual 
Schedule of Activities should be followed, starting at screening visit to ensure participant 
eligibility by randomization visit.
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual Schedule of Activities. To maximize the possibility that these visits 
can be conducted as on-site visits, the windows for visits may be adjusted, upon further guidance 
from the sponsor. This minimizes missing data and preserves the intended conduct of the study.
This table describes the allowed adjustments to visit windows.
Visit Number
Tolerance
Visit 1 through Visit 13 
or higher treatment 
cycles
Visit performed within 7 days before the intended date, or up to 7 days after the 
intended date whenever possible and safe to do so.
As drug administration should be continuously, this visit window adjustment won’t apply for 
drug dispense, which will follow original schedule if no signal for dose interruption per 
investigator discretion. For participants whose visits have extended windows, additional study 

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intervention may need to be provided to avoid interruption and maintain overall integrity of the 
study. 
Documentation
Changes to study conduct will be documented
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records.
Source documents at alternate locations
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 

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Appendix P
Protocol JZNJ Amendment (b) Summary: A Phase 2 Study of Oral 
LOXO-305 in Patients with Previously Treated Chronic Lymphocytic 
Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin 
Lymphoma (NHL)
Overview
Protocol J2N-MC-JZNJ (a), A Phase 2 Study of Oral LOXO-305 in Patients with Previously 
Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-
Hodgkin Lymphoma (NHL), has been amended.  The new protocol is indicated by amendment 
(b) and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:

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Amendment Summary for Protocol J2N-MC-JZNJ Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Synopsis and Section 4.1 Inclusion Criteria 1
“Documented evidence of radiographically and/or histologically confirmed 
disease progression” was clarified as “Documented evidence of patients 
having failed or intolerant”.
Modified wording in Inclusion Criteria 1 of Section 4.1 to keep consistent 
with Synopsis.
Clarification and to keep 
consistent with synopsis
Synopsis and Section 4.1 Inclusion Criteria 5
Added a time limitation to clarify the definition of “adequate hematologic 
status”.
Clarification
Synopsis STUDY ASSESSMENTS
Added “optional based on clinical indicated” to clarify the initial response 
evaluation and shorten response evaluation time window for the following 
evaluation.
Added visit interval for ≥2 years LTFU for clarification.
Clarification
Synopsis STATISTICAL METHODS Efficacy 
Analyses and Section 8.3.3 Efficacy Analyses
PR-L was removed from ORR calculation.
Follow with China 
clinical trial practice
Section 4 SELECTION OF STUDY 
POPULATION
Added “except other specified in protocol” for clarification.
Clarification
Section 4.1 Inclusion Criteria 4
Added “of the Protocol” to keep consistent with synopsis.
To keep consistent with 
synopsis
Section 5 ENROLLMENT PROCEDURES
Modified wording for clarification.
Clarification
Section 6.2.2 Dose Delays/Modifications
Added wording to clarify the operation.
Clarification
Section 6.3.1 General
Added “whichever is shorter” to clarify the definition of concomitant 
medications.
Clarification
Section 6.3.2 Allowed Concomitant Medications
Added wording to clarify the operation of local treatment for target lesion.
Clarification
Section 7 Table 7.1 Schedule of Assessments 
(SOA)
Shorten visit window for cycles 13 and higher;
Modified “bone marrow aspirate and biopsy” to be “bone marrow aspirate 
and/or biopsy” for clarification;
Added the word “optional” to clarify bone marrow aspirate and/or biopsy is 
optional at PD.
Clarification
Footnote “*” of Table 7.1
Modified the note to keep consistent with section 5.
To keep consistent with 
previous wording
Note of Table 7.1
Added a sentence “Study conduct during exceptional circumstances please 
refer to Appendix O.”
Clarification
Footnote “c” of Table 7.1
Added “pulse is acceptable if patients are not under cardiac arrythmias” to 
clarify the definition of heart rate.
Clarification
Footnote “e” of Table 7.1
Removed “bands” from WBC count differential.
To keep consistent with 
China clinical practice
Footnote “k” of Table 7.1
Minor modification for “t(11;14) status” to direct operation.
Clarification

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 1 0 8
L Y 3 5 2 7 7 2 7
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
F o ot n ote “ m” of Ta ble 7. 1
Mi n or m o dificati o n f or clarificati o n a n d c o nsiste nc y.
Clarificati o n
F o ot n ote “ p ” of Ta ble 7. 1
Mi n or m o dificati o n f or clarificati o n a n d c o nsiste nc y.
Clarificati o n
F o ot n ote “ w” of Ta ble 7. 1
A d de d “t hr o u g h cli nical, i ma gi n g or e n d osc o p y” t o clarif y h o w t o esti mate 
GI i n v ol ve me nt at baseli ne.
Clarificati o n
I m p orta nt ti me p oi nt wit h 
n o ti me wi n d o w
F o ot n ote “a” of Ta ble 7. 2
M o difie d t he w or di n g t o kee p c o nsiste nt wit h t he ta ble.
T o kee p c o nsiste nt wit h 
t he c o nte nt of Ta ble 7. 2
Secti o n 7. 1. 2 Scree ni n g
M o difie d
w or di n g t o kee p c o nsiste nt wit h secti o n 5 a n d Ta ble 7. 1.
T o kee p c o nsiste nt wit h 
pre vi o us w or di n g
Secti o n 7. 1. 3 E nr oll me nt
A d de d “ wit hi n scree ni n g wi n d o w” t o clarif y ti me li mitati o n f or e nr oll me nt.
Clarificati o n
Secti o n 7. 1. 7 Vital Si g ns
M o difie d w or di n g t o kee p c o nsiste nt wit h S O A.
T o kee p c o nsiste nt wit h 
S O A
Secti o n 7. 1. 9 La b orat or y Tests
Re m o ve d “ ba n ds” fr o m W B C c o u nt differe ntial a n d a d de d a “,” after 
“ C 1 D 1”.
T o kee p c o nsiste nt wit h 
S O A
Secti o n 7. 2 P har mac o ki netics
M o difie d t he w or di n g t o kee p c o nsiste nt wit h t he Ta ble 7. 2.
T o kee p c o nsiste nt wit h 
t he c o nte nt of Ta ble 7. 2
Secti o n 7. 4 Ce ntral T u m or Sa m ple S u b missi o n 
( Peri p heral Bl o o d, B o ne Marr o w, Tiss ue)
Se parate d t he para gra p h of M C L t u m o r sa m ple c ollecti o n a n d res p o nse 
assess me nt fro m I n d ole n t N H L a n d m o difie d w or di n g f or clarificati o n.
Clarificati o n
S ecti o n 7. 5 Pat h ol o g y a n d M olec ular Re p orts
M o difie d w or di n g t o kee p c o nsiste nt wit h S O A.
T o kee p c o nsiste nt wit h 
S O A
S ecti o n 7. 6 B o ne Marr o w As pirate a n d Bi o ps y
S ecti o n 7. 7 Gastr oi ntesti nal E n d osc o p y
S ecti o n 7. 8 Ra di ol o gic Disease Assess me nt
S ecti o n 7. 1 1 C o nc o mita nt Me dicati o n
M o difie d w or di n g t o kee p c o nsiste nt wit h Secti o n 6. 3. 1.
T o kee p c o nsiste nt wit h
pre vi o us w or di n g
Secti o n 7. 1 4 Ce ntral C ollecti o n of Ra di o gra p hic 
St u dies a n d Sa m ples
Re m o ve d “a n d t heir ass ociate d re p orts” f or clarificati o n.
Clarificati o n
S ecti o n 7. 1 7 L o n g -Ter m F oll o w - u p
M o difie d w or di n g f or clarificati o n a n d t o kee p c o nsiste nt wit h S y n o psis.
T o kee p c o nsiste nt wit h 
pre vi o us w or di n g
A p pe n di x A Ta ble 1 1. 1 L u ga n o Classificati o n of 
Res p o nse a n d its f o ot n ote
M o difie d s o me err ors a n d a d de d w or di n g base d o n L u ga n o Classificati o n 
f or clarificati o n.
C larificati o n
A p pe n di x B f o ot n ote of Ta ble 1 1. 2
Re place d “ S o urce” wit h “ F or c o m plete I W C L L g ui deli ne, please refer t o” 
f or clarificati o n.
C larificati o n
A p pe n di x C f o ot n ote of Ta ble 1 1. 3
Re place d “ S o urce” wit h “ F or c o m plete I W W M g ui deli ne, please refer t o” 
f or clarificati o n.
C larificati o n
A p pe n di x E Pri or B T K I n hi bit ors
A d de d ge neric na me f or I C P -0 2 2.
C larificati o n
C CI

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Section # and Name
Description of Change
Brief Rationale
Appendix K Table 11.9 Guidelines for Patient 
Sample Collection for Central Analysis
Separated MCL tumor sample collection and response assessment from 
Indolent NHL and modified wording to keep consistent with previous 
content.
Clarification
Appendix O Provisions for Changes in Study 
Conduct During Exceptional Circumstances
Added this appendix to direct the clinical trial operation during exceptional 
circumstances.
To direct operation in 
specific circumstance

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
SYNOPSIS
Inclusion Criteria:
1.
Patients with histologically confirmed B-cell malignancy including:
……
For patients in each Cohort:
•
All patients must have disease requiring treatment;
•
Documented evidence of radiographically and/or histologically confirmed disease 
progression patients having failed or intolerant on the most recent line of therapy or relapse prior 
to study enrollment is required;
……
5.
Adequate hematologic status, defined as the following on or within 7 days of C1D1 
before treatment: 
a.
Absolute neutrophil count (ANC) ≥0.75×109/L without granulocyte-colony stimulating 
factor (GCSF) supporting within 7 days of Screening assessment; the patient may enroll below 
this threshold if there is documented bone marrow involvement considered to impair 
hematopoiesis.
b.
Platelet count ≥50 × 109/L not requiring transfusion support or growth factors supporting 
within 7 days of Screening assessment; the patient may enroll below this threshold if there is 
documented bone marrow involvement considered to impair hematopoiesis.
c.
Hb ≥8 g/dL not requiring transfusion support or growth factors supporting within 7 days 
of Screening assessment; the patient may enroll below this threshold if there is documented 
bone marrow involvement considered to impair hematopoiesis.
d.
Patients must be responsive to blood or platelets transfusion support if given for bone 
marrow involvement induced cytopenias.  Patients refractory to transfusion support are not 
eligible.  See also exclusion criteria item 18.
STUDY ASSESSMENTS:
Efficacy assessments include tumor evaluation (radiologic and laboratory) every 8 weeks 
beginning with Cycle 3 Day 1 (± 7 days) through Cycle 12 Day 1, then ~ every 12 weeks 
thereafter (± 2 weeks) for 1 year, then ~ every 6 cycles (± 4 weeks) thereafter, consistent with 
disease-defined criteria.  An initial response evaluation (optional based on clinical indicated)
may be conducted on Cycle 2 Day 1 (±7 days) with a confirmatory response evaluation 
conducted 4 weeks (Cycle 3 Day 1± 7 days) after the first tumor evaluation that shows a partial 
response (PR) or better, if consistent with local institution and regulatory authority 
requirements.  

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……
All patients will enter Long-term Follow-up (LTFU) with visits ~ every 3 months (±1 month)
for up to 2 years and ~every 6 months (±2 month) thereafter, for confirming the resolution of 
any serious adverse events (SAEs), PD if not occurring on study, subsequent anticancer therapy, 
and survival.  LTFU may be conducted by phone if a patient unable to travel to clinic.
STATISTICAL METHODS:
Efficacy Analyses:
Patients enrolled who meet the criteria for the primary analysis set (PAS) will be included in the 
primary analysis for Cohorts 1 and 2, as defined separately in the statistical analysis plan. 
Overall response rate (ORR) will be assessed using Lugano criteria (Appendix A) or IWCLL 
(Appendix B) including assessment of complete response with incomplete marrow recovery 
(CRi), nodular PR (nPR), and PR with lymphocytosis (PR-L), or IWWM (Appendix C), as 
appropriate to tumor type. The inclusion of PR-L response is added to avoid underestimation of 
true clinical benefit (Cheson et al. 2012).  The estimate of the ORR will be calculated as the 
proportion of patients with best overall response (BOR) of PR-L or better, based on IWCLL, PR 
or better based on Lugano, and minor response or better for WM based on IWWM criteria as 
determined by IRC and by the treating investigator.  The estimates of the ORR will be 
accompanied by a 2-sided 95% confidence interval (CI).
4.
SELECTION OF STUDY POPULATION
Potential patients must sign an informed consent form (ICF) before any study-specific screening tests 
may be conducted, except other specified in protocol.
4.1
Inclusion Criteria
1.
Patients with histologically confirmed B-cell malignancy including:
……
For patients in each Cohort:
•
All patients must have disease requiring treatment;
•
Documented evidence of radiographically and/or histologically confirmed disease 
progression patients having failed or intolerant on the most recent line of therapy or relapse prior 
to study enrollment is required;
Patients in Cohort 1 and 2, relapsed/refractory or intolerant (as per the definitions in 
Appendix D) to a prior BTK inhibitor treatment (investigational or approved, and either alone or 
in combination with other agents) treatment is required. 
……
4
Confirmation of availability of tumor sample along with pathology report for central 
pathology review as described in Section 7.4 of the Protocol for patients enrolled in Cohort 1.
5.
Adequate hematologic status, defined as the following on or within 7 days of C1D1 

J2N-MC-JZNJ (b) Clinical Protocol
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before treatment: 
a.
Absolute neutrophil count (ANC) ≥0.75×109/L without granulocyte-colony stimulating 
factor (GCSF) supporting within 7 days of Screening assessment; the patient may enroll below 
this threshold if there is documented bone marrow involvement considered to impair 
hematopoiesis.
b.
Platelet count ≥50 × 109/L not requiring transfusion support or growth factors supporting 
within 7 days of Screening assessment; the patient may enroll below this threshold if there is 
documented bone marrow involvement considered to impair hematopoiesis.
c.
Hb ≥8 g/dL not requiring transfusion support or growth factors supporting within 7 days 
of Screening assessment; the patient may enroll below this threshold if there is documented 
bone marrow involvement considered to impair hematopoiesis.
d.
Patients must be responsive to blood or platelets transfusion support if given for bone 
marrow involvement induced cytopenias.  Patients refractory to transfusion support are not 
eligible.  See also exclusion criteria item 18.
……
5.
ENROLLMENT PROCEDURES
Patients who cannot complete the procedures within the screening window may be rescreened, 
and certain screening procedures may not need to be repeated, with documented sponsor 
approval. including cCertain procedures that were obtained as part of the patient’s standard care 
prior to providing informed consent for this study with documented sponsor approval.(i.e., 
hematology, imaging), may be utilized for screening or baseline purposes provided the 
procedures met the protocol-specified criteria, and were performed within the time frame 
defined in the Table 7.1.
6.
TREATMENT AND ADMINISTRATION
6.2.2
Dose Delays/Modifications
……
Upon recovery, investigator should discuss with sponsor and the patient may restart therapy as 
outlined in (Table 6.1) if it is considered in his/her best interest to continue therapy and with 
documented sponsor approval.  Any continued dosing before a clinically significant AE recovers 
to Grade 1 or less, or baseline if baseline is Grade 2 or above, should be discussed and get 
documented sponsor approval.  If the AE does not recover to Grade 1 or less, or baseline if 
baseline is Grade 2 within 28 days, the patient will have treatment permanently discontinued, 
unless there is a compelling clinical rationale for dose holding for more than 28 days or 
additional dose reduction(s) articulated by the investigator and approved by the sponsor.  For 
each patient, a maximum of 2 dose reductions will be allowed, unless there is a compelling 
clinical rationale for additional dose reduction(s) articulated by the investigator and approved by 
the sponsor (Table 6.1).
……

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Patients who have been dose-reduced and who tolerate LOXO-305 without toxicity for at least 
2 weeks may be re-escalated to the next higher dose level, not to exceed 200 mg QD, with 
continued re-escalation with the agreement at the discretion of the investigator and approved by 
the sponsor.  If the LOXO-305 dose is reduced for apparent treatment-related toxicity, the dose 
need not be re-escalated.
All dose interruptions and dose modifications and the reasons for those changes will be recorded 
in the Case Report Form (CRF).
6.3.1
General
Concomitant medications will include ongoing medications and all medications that were 
administered within 14 days prior to the planned start of study drug (i.e.,or from Screening 
(whichever is shorter) through the SFU visit (at least 28 days [+7 days] after the last dose of 
study drug) and are to be recorded in the CRF.  These are to include prescription and 
nonprescription medications, transfusions, vitamins, nutritional supplements, and other 
remedies.  Excluded medications are indicated in the Exclusion Criteria (Section 4.2).
6.3.2
Allowed Concomitant Medications
Local treatment while receiving LOXO-305 (e.g., palliative radiation therapy or surgery for 
bone metastases) is permitted with documented sponsor approval.  If the lesion that is to be 
treated is a target lesion, the lesion will be censored at the time of treatment. However, the 
patient may remain on study provided there are other target lesions that can be followed for 
response assessment.; Hhowever, the sponsor recommends holding LOXO-305 for ~3-5 half-
lives before and after radiation therapy or surgery.  Any concern for disease flare due to a 
prolonged LOXO-305 dose interruption should be discussed with the sponsor, who may permit 
holding LOXO-305 for a shorter period of time.
7.
STUDY PROCEDURES AND ASSESSMENT

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Table 7.1
Schedule of Assessments
Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(±2
Days)
D15
(±2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±37 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
Results of tests below are required for enrollment
Informed consent
X
Medical, surgical, 
malignancy 
historya
X
Physical 
examination and 
ECOGb
X
X
X
X
Day 1 each cycle
X
X
Vital signsc
X
X
X
X
Day 1 each cycle
X
X
12-lead ECGd
X
X
X
Day 1 every other cycle, C2
through 12, then as 
clinically indicated
X
X
Hematologye
X
X
X
X
Day 1 each cycle
X
X
Blood chemistriesf
X
X
X
X
Day 1 each cycle
X
X
Coagulation panelg
X
As clinically indicated
Urinalysish
X
X
Day 1 each cycle through 
C12, then as clinically 
indicated
X
Serum or urine 
pregnancy test (if 
applicable)i
X
Day 1 each cycle
HIVj
X

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Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(±2
Days)
D15
(±2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±37 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
CMV, Hepatitis B 
and Hepatitis C 
testingj
X
Documentation of 
histologic diagnosis 
and relevant
biomarkersk
X
Documentation or sampling required during screening but results not required prior to enrollment
Tumor sample 
obtained for central 
pathology reviewl
X
Bone marrow 
aspirate and/or
biopsym
X
For confirmation of CR and at PD (optional) (refer to Appendix K)
Upper and lower 
endoscopyw
X
For confirmation of CR in MCL patients of Cohort 1 only (refer to Appendix K)
For CLL/SLL
Lymphocyte 
subsetsn
X
Every 8 
weeks 
beginning 
with C3D1 
(±7 days)
Every 12 weeks 
(±2 weeks) 
beginning with 
C13D1 for 1 
year, then every 
6 cycles (±4 
weeks) after
X
Xx

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Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(±2
Days)
D15
(±2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±37 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
For patients with 
known 
paraprotein: 
SPEP, serum 
immunofixation, 
serum FLC, 
quantitative
Immunoglobulins, 
total proteino
X
Every 8 
weeks 
beginning 
with C3D1 
(±7 days)
Every 12 weeks 
(±2 weeks) 
beginning with 
C13D1 for 1 
year, then every 
6 cycles (±4 
weeks) after
X
Xx
Radiologic 
disease 
assessmentp
X
Every 8 
weeks 
beginning 
with C3D1
(±7 days)
Every 12 
weeks
(±2 weeks) 
beginning 
with C13D1
for 1 year, 
then every 6 
cycles
(±4 week
s) after
X
Xx
Items starting with Cycle 1
Blood samples 
for PKq
Refer to Table 7.2
Telephone 
follow-up
X
X
Survival statusr
X

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Evaluation
Screening*
Cycle 1
(D1-D28)
Cycles 2 
through 
12
Cycles 13 
and Higher
EOT**
SFU
LTFU
801
802 - 8XX
Visit Window
D0
(-28 Days)
D1
(-2
Days)
D8
(±2
Days)
D15
(±2
Days)
D22
(±2
Days)
D1
(± 3
Days)
D1
(±37 Days)
≤7 days 
after last dose 
or decision to 
terminate 
treatment
28 days (+7 
days) after last 
dose of study 
drug
Every 3 months
± 1 month for 
up to 2 years 
after last dose 
of study drug
LOXO-305 
administration
X
X
Patient dosing 
diarys
X
X
Concomitant 
medicationt
X
X
Adverse eventu
X
X
EORTC QLQ-
C30v
X
X
X
X
EORTC IL63 
(MCL patients 
only)v
X
X
X
X
……
*
Certain procedures that were obtained as part of the patient’s standard care prior to providing informed consent for this study (i.e., hematology, imaging), may 
be utilized for screening or baseline purposes provided the procedures met the protocol-specified criteria.Screening studies may be done on C1D1 prior to dosing of 
LOXO-305 with sponsor approval. In Table 7.1, if results are noted as required prior to starting LOXO-305, results of these studies may be required before patients may 
be officially enrolled.
……
Note:  Study conduct during exceptional circumstances please refer to Appendix O.
……
c.
Systolic and diastolic blood pressure, heart rate (pulse is acceptable if patients are not under cardiac arrythmias), respiratory rate, and body temperature.  
•
For vital signs assessed at PK time points, vital signs including weight should be conducted prior to actual PK blood sampling pre-dose (initial dose) 
(up to 4 hours pre-dose, as close to dosing as possible is preferred), and on C1D1 and C1D8 vital signs should also be conducted post-dose at 2 hours 
(±15 minutes).
•
For vital signs assessed at non-PK time points: pre-dose (up to 4 hours pre-dose, as close to dosing as possible is preferred)
……

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 1 1 8
L Y 3 5 2 7 7 2 7
e.
He mat ol o g y i ncl u des he m o gl o bi n, he mat ocrit, R B C c o u nt, W B C c o u nt, platelet c o u nt, perce nt or a bs ol ute W B C c o u nt differe ntial ( ne utr o p hils, ba n ds, 
l ym p h oc y tes, e osi n o p hils, bas o p hils, a n d m o n oc ytes).  F or W M a n d C L L/ S L L patie nts, bl o o d sa m ples s h o ul d als o be pr o vi de d f or ce ntral assess me nt o n C 1 D 1, 
± 7 da ys of eac h ra di ol o gic disease assess me nt a n d at disease pr o gressi o n.  Scree ni n g res ults perf or me d wit hi n 7 da ys of C 1 D 1 are acce pta ble as C 1 D 1 res ults.  
Please e nter t he data c orrectl y i n t he C R F.
… …
k.
A n o n y mize d/re dacte d pat h ol o g y re p ort(s) c o nfir mi n g hist ol o gic dia g n osis a n d t he stat us of a n y k n o w n bi o mar kers (e. g., FI S H, I G V H, p 5 3, kar y ot y p e f or 
C L L/ S L L, M Y D 8 8, C X C R 4 f or W M, Ki 6 7 stai ni n g f or M C L) s h o ul d be s u b mitte d.  I n patie nts wit h M C L, d oc u me ntati o n o f c ycli n D 1 o vere x pressi o n a n d/ or
t( 1 1; 1 4) p ositi ve stat us m ust be pr o vi de d eit her as a pat h ol o g y re p ort fr o m a n yti me i n t he patie nt’s past or fr o m c urre nt tiss ue testi n g. Patients  ma y n ot be 
e nr olle d wit h o ut d oc u me ntati o n of C ycli n D 1 a n d / or t( 1 1; 1 4) status. I n patie nts wit h W M, d oc u me ntati o n of M Y D 8 8 m utati o n m ust be pr o vi de d eit her as a 
pat h ol o g y re p ort fr o m t he patie nt’s past hist or y or fr o m c urre nt tiss ue testi n g. Patie nts wit h W M ma y n ot be e nr olle d wit h o ut d oc u me ntati o n of M Y D 8 8 
m utati o n.
… …
m.
F or C L L/ S L L, W M, i n d ole nt N H L, a n d selecte d cases of hi g h - gr a de N H L, baseli ne b o ne marr o w as pirate a n d / or bi o ps y is re q uire d u nless was alrea d y d o ne 
after t he last treat me nt or w hile pr o gressi n g o n t he m ost rece nt a n d wit hi n 9 0 da ys of Scree ni n g.  B o ne marr o w bi o psies perf o r me d w hile still recei vi n g t he 
m ost rece nt treat me nt are all o we d if t he patie nt was pr o gr essi n g at t he ti me of t he b o ne marr o w bi o ps y.  A de q uate a m o u nt of sa m ples, fres h or arc hi ve d, m ust 
be a vaila ble as defi ne d i n t he La b orat or y Ma n ual f or ce ntral baseli ne assess me nt.  Refer t o Secti o n 7. 4 , A p pe n di x K a n d t he La b orat or y Ma n ual f or g ui da nce 
re gar di n g re q uire me nts f or sa m ple s u b missi o n base d o n hist ol o g y.  Patie nts wit h ot her res p o nse assess me nts c o nsiste nt wit h C R m a y  nee d t o u n der g o b o ne 
marr o w bi o ps y a n d / or as pirati o n i n or der t o c o nfir m C R (refer t o Secti o n 7. 4 a n d A p pe n di x K ). All M C L patie nts w h ose ot her res p o nse assess me nt are 
c o nsiste nt wit h C R a n d k n o w n b o ne marr o w i n v ol ve me nt at baseli ne m ust u n der g o a b o ne marr o w bi o ps y a n d as pirati o n i n or der t o c o nfir m C R.
… …
p.
Refer t o Secti o n 7. 8 a n d A p pe n di x A , A p pe n di x B , a n d A p pe n di x C f or s pecific ra di ol o gic disease assess me nt g ui deli nes.  I n vesti gat ors ma y c o n d uct a n i nitial 
t u m or e val uati o n o n C 2 D 1 ( ± 7 da ys) ( o pti o nal base d o n cli nical i n dicate d) a n d a c o nfir mat or y t u m or e val uati o n a mi ni m u m of 4 wee ks ( C 3 D 1 ±7 da y s) after 
t he first t u m or e val uati on t hat s h o ws a C R or P R b y disease-s pecific criteria, if c o nsiste nt wit h l ocal re g ulat or y a ut h orit y re q uire me nts.  At baseli ne i ma gi n g 
s h o ul d i ncl u de c hest, a b d o me n, a n d pel vis, a n d ot her areas wit h disease i n v ol ve me nt. F oll o w-u p i ma gi n g i nc l u des c hest, a b d o me n, pel vis a n d a n y areas k n o w n 
t o ha ve disease i n v ol ve me nt at baseli ne. Ot her areas s uc h as t he nec k, hea d a n d e xtre mities ma y be i ma ge d if disease i n v ol ve me nt is s us pecte d.  F or patie nts 
(e. g., C L L or W M) wit h d oc u me nte d disease i n v ol vi ng bl o o d/ b o ne marr o w b ut n o d oc u me nte d baseli ne ra di o gra p hic fi n di n gs a n d w here ra di ol o g y is n ot 
re q uire d f or r o uti ne res p o nse assess me nt, i ma gi n g is t o be perf or me d e ver y 6 c ycles (i.e., e n d of c ycle 6, e n d of c ycle 1 2) f or t he d urati o n of st u d y treat me nt.   
Cli nical P D s h o ul d be assesse d wit h ra di o gra p hic i ma gi n g u nless m ost rece nt i ma gi n g was perf or me d wit hi n 2 8 da ys of cli nical P D.
… …
w.
Patie nts wit h M C L i n C o h ort 1 wit h hist or y or e vi de nce of GI i n v ol ve me nt o n baseli ne assess me nt ma y re q uire a p pr o priate u p per a n d/ or l o wer e n d osc o p y 
pr oce d ure (if it is cli nicall y safe) d uri n g scree ni n g wit h bi o ps y t o d oc u me nt i n v ol ve me nt at baseli ne.  Patie nts wit h M C L i n C o h ort 1 wit h k n o w n or e vi de nce 
of GI i n v ol ve me nt (t hr o u g h cli nical, i ma gi n g or e n d osc o p y) at baseli n e, w h ose ot her disease assess me nts s u g gest C R m ust u n der g o 
Es o p ha g o gastr o d u o de n osc o p y a n d/ or C ol o n osc o p y wit h ra n d o m se g me ntal bi o psies t o c o nfir m C R (if it is cli nicall y safe).

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 1 1 9
L Y 3 5 2 7 7 2 7
C CI

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7.1
Study Assessments
7.1.2
Screening
The screening procedures must be conducted within 28 days prior to C1D1, unless otherwise 
noted.  Patients who cannot complete the procedures within the screening window and who do 
not meet the criteria for participation in this study (screen failure) may be rescreened after 
discussion with and permission from the Lilly CRP or designee, and certain screening 
procedures may not need to be repeated, with documented sponsor approval. including cCertain 
procedures (i.e., hematology, imaging) that were obtained as part of the patient’s standard care 
prior to providing informed consent for this study, may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed within 
the time frame defined in the Table 7.1 with documented sponsor approval.  The results should 
be recorded in the Screening set of CRFs.
7.1.3
Enrollment
Enrollment procedures will be conducted in accordance with the Schedule of Assessments 
(Table 7.1).  Patients who meet eligibility criteria outlined in Section 4 will be enrolled in this 
study.  The investigator may repeat qualifying laboratory tests and vital signs/ECGs prior to 
enrollment and within Screening window, if a non-qualifying finding is considered an error, 
and/or if an acute finding is likely to meet eligibility criteria on repeat testing.
7.1.7
Vital Signs
Vital signs will be measured pre-dose in accordance with the Schedule of Assessments 
(Table 7.1) and should include systolic and diastolic blood pressure, heart rate (pulse is 
acceptable if patients are not under cardiac arrythmias), respiratory rate, and body temperature.
……
7.1.9
Laboratory Tests
……
•
Hematology
For all enrolled patients:  Hematology should be assessed locally in accordance with the 
Schedule of Assessments (Table 7.1) and should include assessment of the following: 
hemoglobin, hematocrit, RBC count, WBC count, platelet count, percent or absolute WBC 
count differential (neutrophils, bands, lymphocytes, eosinophils, basophils, and monocytes).
For WM and CLL/SLL patients:  Blood samples for central assessment should also be collected 
on C1D1, ±7 days of each radiologic disease assessment and at disease progression.
……
7.2
Pharmacokinetics
……

J 2 N -M C -J Z N J ( b ) Cli ni c al Pr ot o c ol
P a g e 1 2 1
L Y 3 5 2 7 7 2 7
… …
7. 4
Ce ntr al T u m or S a m ple S u b missi o n ( Peri p her al Bl o o d, B o ne M arr o w, Tiss ue)
A de q uate tiss ue sa m ples at scree ni n g are re q uire d fr om pat ient s e nr olle d i n C o h ort 1 f or ce ntral 
pat h ol o g y  re vie w t o be perf or me d retr os pecti vel y.  P atie nts wit h ina de q uate ti ss ue sa m ple 
a vaila bilit y ma y st ill be e nr o lle d i n C o h ort 3 if ot her eli gibili t y criteria ha ve bee n c hec ke d.  
F or pati e nts e nr olli n g wit h M C L , n o d al  tiss ue is preferre d ( vs marr o w) a n d m ust i ncl u de u p t o 
1 0 u nstai ne d sli des ( or re prese ntati ve sect i ons of arc hi ve d paraffi n bl o c k).  De-i de ntifie d 
s ur gical pat h olo g y  re p orts of t he patie nt’s dia g n osis of l y m p h o ma a n d a ncillar y st u dies , s uc h as 
flo w c y t o metr y, i m m u n o hist oc he mistr y, FI S H, c yt o ge netics, or mol ec ular st u dies, w hic h were 
use d t o esta blis h t he dia g n osis are als o re q ueste d.
F or M C L: f or Scree ni n g, b o ne marr o w bi o ps y  is re qui r e d for baseli ne assess me nt, a n d patie nts 
i n C o h ort 1 wit h k n o w n or e vi de nce of GI i n v o l ve me nt a p pr o priate u p per a n d/ or l o wer 
e n d osc o p y ma y be perf or me d if it is cli nicall y safe f or baseli ne assess me nt a n d if n ot perf or me d 
wi t hi n 4 2 da ys of e nr oll me nt. A de q uate sa m ple as La b Ma n ual is re q uire d t o s u b mit f or ce ntral 
assess me nt.
F or res p o nse assess me nt: B o ne marr o w bi o ps y  s h o uld be d o ne as a p pr o priate f or c o nfir mat i on 
of  C R if k n o w n disease i n v ol ve me nt at baseli ne.  Ot her assess me nts s u g gest C R, 
es o p ha g o ga str o d u o de n osc o p y a n d c ol on osc o p y  wit h ra n d o m se g me ntal bio psies i s re q uire d, if 
cli nicall y safe, f or c o nfir mat i on of C R i n C o h ort 1 M C L pat ient s wit h k n o w n GI i n v ol ve me nt at 
baseli ne. A de q uate sa m ple as La b Ma n ual is re q uire d t o s u b mit f or ce ntral re vie w.   B o ne 
marr o w a n d e n d osc o p y  for l o c al  res p o nse assess me nt at t he ti me p oi nts s pecifie d i n Ta ble 7. 1
a n d A p pe n di x K are als o re q uire d.
F or C L L/ S L L:  f or Scree ni n g, peri p heral bl o o d a n d b o ne marr o w bi o ps y with as pirate are 
re q uire d f or baseli ne t u m or assess me nt , a n d a de q uate sa m ple as A p pe n di x K a n d La b Ma n ual 
re q uire d als o s h o ul d s u b mitt e d f or ce ntral assess me nt.
F or res p o nse assess me nt:  Peri p heral bl o o d is re q uire d.  B o ne marr o w bi o ps y a n d as pirat i on is 
re q uir e d for c o nfi r mat i on of C R a n d s h o ul d be d o ne i n a p pr o priate setti n gs w here all ot her 
assess me nts s u g gest C R a n d a de q uate sa m ple as A p pe n di x K La b Ma n ual is re q uire d t o s u b mit 
f or ce ntral re vie w.  Perip heral bl o o d a n d b o ne marr o w f or l ocal res p o nse assess me nt at t he ti me
p oi nts s pecifie d i n Ta ble 7. 1 a nd A p pe n di x K are als o re q uire d.
F or W M:  f or Scree ni n g, peri p heral bl o o d a n d b o ne marr o w bi o ps y wi t h as pirate are re q uire d
f or baseli ne assess me nt a n d a de q uate sa m ple as A p pe n di x K a n d La b Ma n ual is re q uire d t o 
C CI

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submit for central assessment.
For response assessment:  Peripheral blood is required.  Bone marrow biopsy and aspiration is 
required for confirmation of CR and should be done in appropriate settings where all other 
assessments suggest CR and adequate sample as Appendix K and Lab Manual is required to 
submit for central review.  Peripheral blood and bone marrow for local response assessment at 
the time points specified in Table 7.1 and Appendix K are also required.
For Iindolent NHL (e.g., MZL, follicular lymphoma [FL]):  for Screening: Bone marrow biopsy 
is required for marrow involvement assessment and adequate sample as Appendix K and Lab 
Manual required also should submit for central assessment.
For response assessment: Bone marrow biopsy and aspiration is required for confirmation of CR 
and should be done in appropriate settings where if known disease involvement at baseline and 
all other assessments suggest CR and adequate sample as Appendix K and Lab Manual required 
also should submit for central assessment.
For non-MCL Hhigh grade NHL (e.g., MCL, diffuse large B cell lymphoma [DLBCL]):  For 
Screening: Bone marrow biopsy is required only if clinical suggestion of marrow involvement is 
noted, i.e., unexplained cytopenia, and adequate sample as Appendix K and Lab Manual 
required also should submit for central assessment.
For MCL patients in Cohort 1 with known or evidence of GI involvement appropriate upper 
and/or lower endoscopy may be performed if it is clinically safe for baseline assessment, if not 
performed within 42 days of enrollment.
For response assessment (non-MCL):  Bone marrow biopsy and aspiration should be done as 
appropriate for confirmation of response assessment only if known disease involvement at 
baseline; per Lugano staging criteria, positron emission tomography (PET) scan assessment of 
marrow response is acceptable.  
For MCL response assessment:  Bone marrow biopsy and aspiration must be done for 
confirmation of CR and adequate sample is required to submit for central review. 
Esophagogastroduodenoscopy and colonoscopy with random segmental biopsies is required, if 
clinically safe, for confirmation of CR in MCL patients with known GI involvement at baseline.
7.5
Pathology and Molecular Reports
Anonymized/redacted pathology report(s) confirming histologic diagnosis and relevant 
biomarkers (e.g., FISH, IGVH, p53, karyotype for CLL/SLL, MYD88, CXCR4 status for WM, 
Ki67 staining for MCL) should be submitted.  For patients with MCL, documentation of Cyclin 
D1 overexpression and/or t(11;14) positive status must be provided either from any time in the 
patient’s history or from current biopsy studies in order for enrollment to proceed.  For patients 
with WM, documentation of MYD88 mutation must be provided either from any time in the 
patient’s history or from current biopsies studies in order for the patient to proceed.
7.6
Bone Marrow Aspirate and Biopsy
For patients enrolled with CLL/SLL, WM, low grade NHL, and selected high grade NHL (refer 
to Section 7.4) with unexplained cytopenia or suspected bone marrow involvement:  A bone 

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marrow aspirate and/or biopsy should be collected during Screening, for confirmation of CR and 
(optional) at disease progression in accordance with the Schedule of Assessments (Table 7.1).  
All MCL patients, whose other response assessments are consistent with CR and known disease 
involvement at baseline, must undergo bone marrow biopsy and aspiration to confirm CR.  
Samples for central assessment should also be collected in accordance with the Schedule of 
Assessments (Table 7.1) and outlined in Section 7.4 “Central Tumor Sample submission”.  If a 
bone marrow biopsy and/or aspiration was done after the last treatment or while progressing on 
the most recent treatment and within 90 days of Screening and samples are available of 
sufficient quality and quantity for molecularcentral analysis, these do not need to be repeated 
during Screening.  Guidance on sample collection and timing is provided in Appendix K and the 
Laboratory Manual.
7.7
Gastrointestinal Endoscopy
For MCL patients in Cohort 1 with known or evidence of GI involvement appropriate upper 
and/or lower endoscopy may be performed if it is clinically safe for baseline assessment, if not 
performed within 42 days of enrollment.  For enrolled patients with MCL with known GI 
involvement (through clinical, imagine or endoscopy) at baseline in Cohort 1, who are in 
radiographic and bone marrow CR, esophagogastroduodenoscopy and colonoscopy with random 
segmental biopsies must be performed as appropriately, to evaluate for GI involvement with 
MCL and to confirm CR.
7.8
Radiologic Disease Assessment
Radiologic disease assessment will be conducted by the investigator in accordance with the 
Schedule of Assessments (Table 7.1) and the Imaging Manual.  Investigators should use the 
same method consistently for an individual patient throughout the study.  For NHL, the 
preferred imaging is PET/CT, and appropriate method in accordance with Lugano guidance 
should be selected based on patients pathologic diagnosis, FDG avidity and lesion location etc..  
For patients with NHL, baseline scans should assess the chest, abdomen, and pelvis.  Other areas 
such as the neck, head and extremities should be scanned should there be known disease present.  
Follow up CT scans may be limited to chest, abdomen and pelvis as well as areas of known 
measurable and non-measurable disease. Assessments of both measurable and non-measurable 
disease will be made by the investigator using criteria as appropriate to cancer type; SLL 
response should be assessed by IWCLL criteria.  The following Appendices should be referred 
to for specific radiologic disease assessment information:

Appendix A
Lugano Classification of Response in Non-Hodgkin Lymphoma

Appendix B
Chronic Lymphocytic Leukemia Response Assessment (IWCLL)

Appendix C
Waldenström Macroglobulinemia Response Assessment (IWWM)
For patients (e.g., CLL or WM) with documented disease involving blood/bone marrow but no 
documented baseline radiographic findings and where radiology is not required for routine 
response assessment, imaging is to be performed every 6 cycles (i.e., end of Cycle 6, end of 
Cycle 12) for the duration of receipt of study treatment.  If tumor involvement is identified 
during routine assessments, then the radiographic assessment schedule will revert to the standard 

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schedule.
In addition, investigators may conduct an initial tumor evaluation on C2D1 (±7 days) (optional 
based on clinical indicated) and a confirmatory tumor evaluation a minimum of 4 weeks 
(C3D1±7d) after the first tumor evaluation that shows a CR or PR by disease-specific criteria, if 
consistent with local regulatory authority requirements.  
……
Patients who are unable to undergo CT scans with contrast due to allergy to contrast dye, may 
substitute magnetic resonance imaging (MRI) with gadolinium or appropriate method per 
investigator discretion and should discuss with sponsor.
……
7.11
Concomitant Medication
Concomitant medications should be recorded in accordance with the Schedule of Assessments 
(Table 7.1).
All medications that were used from 14 days prior to the planned start of study drug or from 
Screening (whichever is shorter)enrollment through SFU (at least 28 days [+7 days] after the 
last dose of study drug) will be recorded in the CRF.  These are to include prescription and 
nonprescription medications, transfusions, vitamins and nutritional supplements, and other 
remedies.  Excluded prior medications are excluded via the eligibility criteria (Section 4.2).  
Additional guidance regarding concomitant medications is provided in Section 6.3.
……
7.14
Central Collection of Radiographic Studies and Samples
Baseline screening radiographic studies and all subsequent radiographic studies and their 
associated reports will be collected for independent radiological review.
Baseline and subsequent samples (peripheral blood, bone marrow aspiration, and biopsy and/or 
tissue samples) required for response assessment according to disease-defined criteria will be 
collected.
……
7.17
Long-Term Follow-up
The LTFU assessments and procedures will be conducted in accordance with the Schedule of 
Assessments (Table 7.1).  After treatment discontinuation, LTFU will occur approximately 
every 3 months (±1 month) for up to 2 years and every 6 months (±2 month) thereafter, until the 
patient experiences PD, withdraws consent for further participation, is lost to follow-up, has 
died, or close of the study.
Assessments may include: subsequent anticancer therapy(ies) and survival status.  LTFU may be 
conducted by phone.  For any patient who is lost to follow-up, the study site will attempt to 
ascertain survival information via public database search.  If survival status still cannot be 
ascertained, patients will be considered lost to follow-up and will be censored appropriately.

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If a patient discontinues study treatment for reasons other than PD, withdrawal of consent or 
initiation of a new anticancer therapy(ies), the patient is required to undergo disease assessment 
by imaging as specified in Appendix A, Appendix B, and Appendix C until PD (even if PD 
occurs after 2 years), withdrawal of consent, or initiation of a new anticancer therapy(ies), 
utilizing the same modality(ies) used for the baseline imaging assessment.
8.3.3
Efficacy Analyses
……
ORR will be assessed using Lugano criteria (Appendix A) or IWCLL (Appendix B) including 
assessment of complete response with incomplete marrow recovery (CRi), nodular PR (nPR),
and PR with lymphocytosis (PR-L), or IWWM (Appendix C), as appropriate to tumor type.  The 
inclusion of PR-L response is added to avoid underestimation of true clinical benefit (Cheson et 
al. 2012).  The estimate of the ORR will be calculated as the proportion of patients with best 
overall response (BOR) of PR-L or better, based on IWCLL, PR or better based on Lugano, and 
minor response or better for WM based on IWWM criteria as determined by IRC and by the 
treating investigator.  The estimates of the ORR will be accompanied by a 2-sided 95% CI.  
Waterfall plots will be used to depict graphically the maximum decrease from baseline in the 
sum of product diameters (SPD) of target lesions.
DOR will be calculated for patients who achieve a response of PR or better (PR-L or better for 
CLL/SLL, minor response or better for WM)……

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11.
APPENDICES
Appendix A
Lugano Classification of Response in Non-Hodgkin Lymphoma
Table 11.1
Lugano Classification of Response
Response and Site
PET-CT–Based Response
CT-Based Response
Complete a
Complete metabolic response
Complete radiologic response (all of the following)
Lymph nodes and extra 
lymphatic sites
Score 1, 2, or 3* with or without a residual mass on 5PS†
It is recognized that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation within spleen or 
marrow (e.g., with chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal mediastinum and/or 
liver. In this circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no greater than 
surrounding normal tissue even if the tissue has high physiologic 
uptake
Target nodes/nodal masses must regress to ≤1.5 cm in LDi
No extralymphatic sites of disease
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Nonmeasured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in marrow
Normal by morphology; if indeterminate, IHC negative
Partial
Partial metabolic response
Partial remission (all of the following):
Lymph nodes and 
extralymphatic sites
Score 4 or 5† with reduced uptake compared with baseline and 
residual mass(es) of any size
At interim, these findings suggest responding disease
At end of treatment, these findings indicate residual disease
≥50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites
When a lesion is too small to measure on CT, assign 5 mm × 5 mm 
as the default value
When no longer visible, 0 × 0 mm
For a node >5 mm × 5 mm, but smaller than normal, use actual 
measurement for calculation
Absent/normal, regressed, but no increase
Spleen must have regressed by >50% in length beyond normal
Nonmeasured lesions 
Not applicable
Absent/normal, regressed, but no increase
Organ enlargement
Not applicable
Spleen must have regressed by >50% in length beyond normal

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Response and Site
PET-CT–Based Response
CT-Based Response
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in normal marrow, but 
reduced compared with baseline (diffuse uptake compatible with 
reactive changes from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the context of a nodal 
response, consideration should be given to further evaluation with 
MRI or biopsy or an interval scan
Not applicable
No response or stable 
disease
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 with no significant change in FDG uptake from 
baseline at interim or end of treatment
<50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met
Nonmeasured lesions
Not applicable
No increase consistent with progression
Organ enlargement
Not applicable
No increase consistent with progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 1 of the following PPD 
i
Individual target 
nodes/nodal masses 
Extranodal lesions
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or
New FDG-avid foci consistent with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be abnormal with: LDi >1.5 cm 
and
Increase by ≥50% from PPD nadir and an increase in LDi or SDi 
from nadir
0.5 cm for lesions ≤2 cm
1.0 cm for lesions >2 cm
In the setting of splenomegaly, the splenic length must increase 
by >50% of the extent of its prior increase beyond baseline 
(e.g., a 15-cm spleen must increase to
>16 cm). If no prior splenomegaly, must increase by at least 
2 cm from baseline
New or recurrent splenomegaly
New or clear progression of preexisting nonmeasured lesions
Nonmeasured lesions
None
New or clear progression of preexisting nonmeasured lesions

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Response and Site
PET-CT–Based Response
CT-Based Response
New lesions
New FDG-avid foci consistent with lymphoma rather than another 
etiology (e.g., infection, inflammation). If uncertain regarding 
etiology of new lesions, biopsy or interval scan may be considered
Regrowth of previously resolved lesions
A new node >1.5 cm in any axis
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any 
axis, its presence must be unequivocal and must be 
attributable to lymphoma
Assessable disease of any size unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
……
Source: For complete Lugano Classification, please refer to (Cheson et al. 2014).

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Appendix B
Chronic Lymphocytic Leukemia Response Assessment (IWCLL)
……
Source: For complete IWCLL guideline, please refer to (Hallek et al. 2018).
Appendix C
Waldenström Macroglobulinemia Response Assessment (IWWM)
……
Source: For complete IWWM guideline, please refer to Anderson, J Natl Compr Canc Netw. 2012; 10(10):1211-
1219.
Appendix E
Prior BTK Inhibitors
Prior BTK inhibitors used in the treatment of CLL/SLL or NHL include, but are not limited to:

Acalabrutinib

DTRMWXHS-12

GDC-0853

Ibrutinib

Orelabrutinib (ICP-022)

SHR1459

TG-1701

Zanubrutinib (BGB-3111)

Evobrutinib (M7583)

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Appendix K
Guidelines for Patient Sample Collection for Central Analysis
Table 11.9
Guidelines for Patient Sample Collection for Central Analysis
Tumor Type
Time Point
Peripheral Blooda
Bone Marrowa
Lymph Node/Tumor 
Tissue
MCL
Baseline
Required unless available after last 
treatment or while progressing on the most 
recent treatment and performed within 90 
days
Required for patients 
enrolled in Cohort 1 for 
central pathology review
Response time points
Required to confirm CR if known disease 
involvement at baseline
Progression
Optional
CLL/SLL
Baseline
Required for response assessmenta,b
Required unless available after last 
treatment or while progressing on the most 
recent treatment and performed within 90 
days
Response time points
Required for response assessmenta,b c
Required at CRa
Progression
Required for response assessmenta,b
Optional
WM
Baseline
Required for response assessmenta,b
Required unless available after last 
treatment or while progressing on the most 
recent treatment and performed within 90 
days
Response time points
Required for response assessmenta,b
Required at CRa
Progression
Required for response assessmenta,b
Optional
Indolent NHL 
(e.g., MZL, FL)c
Baseline
Required unless available after last 
treatment or while progressing on the most 
recent treatment and performed within 90 
days

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Tumor Type
Time Point
Peripheral Blooda
Bone Marrowa
Lymph Node/Tumor 
Tissue
Response time points
Required to confirm CR if known disease 
involvement at baseline
Progression
Optional
Non-MCL High 
grade NHL (e.g., 
MCL, DLBCL)c
Baseline
May be required if unexplained cytopenia 
present at screening suggestive of bone 
marrow involvement unless available after 
last treatment or while progressing on the 
most recent treatment and performed within 
90 days.
Required for patients 
enrolled in Cohort 1 for 
central pathology review
Response time points
MCL: patients, required to confirm CR;
Non-MCL: patients, rRequired at CR only 
if known disease involvement at baseline, 
per Lugano staging criteria, positron 
emission tomography (PET) scan 
assessment of marrow response is 
acceptable a
Progression
Optional
Abbreviations:  CLL = chronic lymphocytic leukemia; CR = complete remission; DLBCL = diffuse large b cell lymphoma; FL = Follicular lymphoma; MCL = mantle 
cell lymphoma; MZL = marginal zone lymphoma; NHL = non-Hodgkin lymphomas; SLL = small lymphocytic lymphoma; WM = Waldenström macroglobulinemia.
a
Indicates local collection and assessment as well. Sample collection for local tumor assessment is also needed.
b
Laboratory studies for response assessment includes blood count with differential for CLL patients and SPEP/immunofixation/serum free light 
chains/quantitative immunoglobulins for WM patients.
c
According to Lugano staging criteria, PET scan can be used to assess bone marrow involvement and response in high grade NHLDLBCL.

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Appendix O
Provisions for Changes in Study Conduct During Exceptional 
Circumstances
Added this appendix to direct clinical trial operation during exceptional circumstances. Detail 
information please refer to Appendix O.

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