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dodge administrative and teaching respon-
sibilities, keep beer in the lab, and collabo-
rate on a series of important experiments.
Key insights into the T-cell receptor and
costimulatory molecules resulted from this
rare intellectual freedom.
The Breakthrough was written just be-
fore Dr. Allison and Tasuku Honjo, MD,
PhD, from Kyoto University, won the
Nobel Prize in Physiology or Medicine
in October 2018 for their work on cancer
immunology. It doesn’t mention the Prize
but instead includes as evidence of re-
cognition of the immunotherapy work a
color plate of a large smiling team win-
ning the 2014 William Coley Award for
discovering PD-1. There was, therefore,
no opportunity to discuss how human
PD-1 discoverers Lieping Chen, MD,
PhD, of Yale University, and Gordon
Freeman, PhD, and Arlene Sharpe, MD,
PhD, of Harvard Medical School were
For patients with previously treated CLL/SLL or B-cell NHL,
LOXO ONCOLOGY IS
RESEARCHING A NEW STRATEGY
TO ADDRESS RESISTANCE
AND INTOLERANCE TO
COVALENT BTK INHIBITORS *
passed over for the 2018 Nobel Prize – a
Swedish Academy omission perhaps
even more egregious than the missed
pass interference call that robbed the
New Orleans Saints of a trip to Super
Bowl LIII. But that controversy, as well as
whether the Nobel Prize’s three-awardee
limit is still meaningful in the 20th cen-
tury, given the many key contributors to
complex work like cancer immunology,
is worth a book unto itself. ●
> NOW
ENROLLING
Investigation into selective non-covalent BTK inhibition may expand
possibilities for patients previously treated with a covalent BTK inhibitor
LOXO-305 is an investigational, selective non-covalent BTK inhibitor currently in clinical development, with
preclinical potency against both wild-type and cysteine-481–mutated BTK (C481S) and improved selectivity
compared with other BTK inhibitors. 1
STUDY DESIGN
A phase 1/2, open-label, first-in-human study designed
to evaluate LOXO-305 in patients with previously treated
CLL/SLL, WM/MCL/MZL, FL, DLBCL, or other B-cell NHL.
Primary Outcome Measures:
Phase 1:
MTD/RP2D
Phase 2:
ORR as assessed by an Independent Review Committee
Secondary Outcome Measures:
Phase 2:
Phase 1:
• ORR as assessed by the Investigator
• Safety
• Best overall response
• PK
• Duration of response
• ORR
• Progression-free survival
• Overall survival
BTK=Bruton’s tyrosine kinase; BTKi=Bruton’s tyrosine kinase inhibitor; CLL=chronic lymphocytic
leukemia; DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; MCL=mantle cell
lymphoma; MTD=maximum tolerated dose; MZL=marginal zone lymphoma; NHL=non-Hodgkin’s
lymphoma; ORR=overall response rate; PK=pharmacokinetics; RP2D=recommended phase 2 dose;
R/R=relapsed/refractory; SLL=small lymphocytic leukemia; WM=Waldenström macroglobulinemia.
Histologically confirmed CLL/SLL and B-cell NHL
NCT03740529:
A Phase 1/2 Study of Oral LOXO-305 in Patients
With Previously Treated CLL/SLL or B-cell NHL
Titration to therapeutic dose based on PK
Identification of MTD/RP2D
life sentences in a Trenton prison, and
will become eligible for parole in the early
25th century. The Breakthrough, like Mr.
Graeber’s previous book, is copiously
annotated, with 107 pages of appendices,
footnotes, references, and indices.
The book is written for the lay reader,
so long sections about basic hematology
and immunology may be a slog for he-
matologists, however engagingly they are
written for a general audience. Still, even
buried within the long explanations
of what different types of white cells
do, there are delightful gems. I did
not know, for example, that in 1968,
when Australian Jacques Miller, AC,
FRS, presented data at an immunology
conference suggesting that there might
be two different types of lymphocytes
called B and T cells, the skeptics – and
they are always present, so illegitimi non
carborundum – unhelpfully pointed out
that “B” and “T” are the first and last
letters of “bullshit.”
I appreciated the book’s enthusi-
asm for its subject, even if I did not
really need to know how a Genentech
researcher scored Imagine Dragons
tickets for his teenage daughter from a
grateful early clinical trial participant.
At times, The Breakthrough falls into
the worn clichés of generalist medi-
cal writing: use of terms like “game
changer,” “revolutionary,” and, well,
“breakthrough,” or descriptions of the
long hours, relentless drive, precise
German-inflected accents, and sartorial
preferences of leading investigators. But
these are minor points, and many read-
ers will find the book interesting.
Lay readers or lab-based investiga-
tors, for example, may be startled to
learn about the games clinicians play
to get patients who are borderline-
eligible into promising clinical trials
(such as repeating labs after fluid
administration, changing concomi-
tant medicines, putting off evaluation
of new symptoms that might lead to
another diagnosis that could make the
patient ineligible, etc.). As industry
sponsors jump on the immunotherapy
bandwagon, a huge number of trials
of with impossible accrual goals are
now proposed for checkpoint inhibi-
tors – highlighting a major problem in
contemporary, herd-mentality–driven
drug development.
My favorite chapter was “Eureka,
Texas,” about James Allison, PhD, who
spent his early days playing blues harp
at honky-tonks and working in a tiny
lab in Smithville, Texas (1970 popula-
tion: 2,959). This lab had been hastily
built by MD Anderson Cancer Center
after receiving an economic stimulus
grant from the state. According to Dr.
Allison, MD Anderson subsequently
“sort of forgot about [us], so they pretty
much left us alone.” The Smithville in-
vestigators were able to skip meetings,
Histologically confirmed CLL/SLL and B-cell NHL
R/R disease, +/- prior BTKi † , CLL/SLL, WM/MCL/MZL,
FL, DLBCL, or other B-cell NHL: wild-type and
C481-mutant, or other patients with clinical rationale
For full eligibility requirements, please visit ClinicalTrials.gov
* eg, Imbruvica® (ibrutinib) and Calquence® (acalabrutinib).
† Prior treatment with any number of approved or investigational covalent or non-covalent
BTK inhibitors is allowed.
Reference: 1. Data on file. BTK001. 2018; Loxo Oncology, Inc.
For more information about enrolling a patient or to participate
as a trial site, visit LoxoBTKtrials.com or call 1-855-LOXO-305.
Copyright © Loxo Oncology, Inc, 2018, All Rights Reserved. LMA-US-BTK-122018-00001
Imbruvica ® is a registered trademark of Pharmacyclics LLC and Janssen Biotech, Inc.
Calquence ® is a registered trademark of AstraZeneca.