An Open Label, Phase 2 Study to Evaluate Efficacy and Safety of Daratumumab in Relapsed or
Refractory Mantle Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular
Lymphoma

Disease evaluations will be performed every 8 weeks (±7 days) in the first 6

months (Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1), followed by every 16

weeks (±7 days) for the next 6 months (Cycle 11 Day 1, Cycle 15 Day 1), and

thereafter every 24 weeks (±14 days). These assessments will be conducted until

disease progression, withdrawal of consent from study participation, or the end

of study. The determination of disease status will be assessed by the

investigator based on the Revised Criteria for Response Assessment (Cheson

2014). Identical methodology should be used for disease assessment at screening

and throughout the course of the study. Radiological and PET scans should be

performed and collected according to instructions from the independent imaging

laboratory. A central review of the response assessments may be performed if

deemed necessary. The major efficacy endpoint, ORR, is defined as the

proportion of subjects who achieve CR or PR.



Secondary efficacy endpoints are:



* Duration of response (DoR) will be duration from the date of the initial

documentation of a response to the date of first documented evidence of PD (or

relapse for subjects who experience CR). For those subjects who are still

without progression/relapse, DoR will be censored at the last adequate tumor

assessment.



* PFS is defined as the duration from the date of the first daratumumab dose to

the date of progression/relapse or death, whichever comes first. For those

subjects who are still alive without progression/relapse, PFS will be censored

at the last adequate tumor assessment.



* Overall survival (OS) is defined as the duration from the date of the first

daratumumab dose to the date of death. For those subjects who are still alive

without progression/relapse, OS will be censored at the last date known to be

alive.



* Time to response is defined as the duration from the date of the first dose

of daratumumab to the earliest date that a response (CR/PR) is first

documented. For non-responders, it will be censored at the date of progressive

disease/relapse or the date of the last adequate disease assessment, whichever

comes first.

PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS

For all subjects, pharmacokinetic samples to determine serum concentration of

daratumumab will be obtained according to Time and Events Schedule. At

specified timepoints, venous blood samples (5 mL per sample) will be collected

to determine serum concentration of daratumumab and the serum will be divided

into 3 aliquots (1 aliquot for pharmacokinetic analysis, 1 aliquot for

antibodies to daratumumab

analysis [when appropriate], and 1 aliquot as a backup).



BIOMARKER EVALUATIONS

During screening, subjects will be required to provide tumor samples (archived

sample mandatory, additional fresh biopsy should be obtained whenever possible)

for assessment of CD38 expression based on central IHC methodology. Fresh tumor

samples can be either lymph node excision or core needle biopsy; fine needle

aspirates are not acceptable. In addition to evaluating CD38 expression, fresh

or archived biopsy samples may be evaluated in all subjects to identify markers

predictive of response to daratumumab or prognostic markers for disease

progression. Paraffin-embedded, formalin-fixed tumor tissue may also be

subjected to DNA (eg, somatic mutations) and RNA analysis (eg, GEP, qRT-PCR, or

RNA-seq) to determine if specific mutations or transcriptomic profiles

(translocations, deletions, inversions, genes involved in B-cell signaling

pathways, CD38 signaling pathways, or others) are associated with daratumumab

response. Comparison of CD38

IHC results may be made to transcriptomic data. In addition to CD38, CD59

expression will be measured by IHC in a designated laboratory as an exploratory

biomarker. CD59 is a complement inhibitory protein and can contribute to

resistance to complement dependent cytotoxicity, which may be important for

daratumumab response. Whole blood samples will be utilized for

immunophenotyping, (performed by flow cytometry or mass

cytometry/time-of-flight mass spectrometry which includes analysis of natural

killer cells, T cells, and B cells as well as other potential immune cell

subpopulations. Plasma samples may be analyzed for proteins associated with

disease progression or daratumumab

response, including complement proteins, sCD38, proteins indicative of infusion

reaction (IL-1, IL-6, TNF*, IFN*, tryptase), and exploratory proteomics.



SAFETY EVALUATIONS

Safety will be measured by adverse events, laboratory test results, ECGs, vital

sign measurements, physical examination findings, and assessment of ECOG

performance status score.