1. 24 ICT l August 2015
Fail Safe
A pivotal Phase 3 study for refractory patients with acute
myeloid leukaemia is looking to steer clear of control group
and endpoint traps, in order to significantly increase the
number of patients eligible for curative stem cell regimens
ICT mAb Trials
myeloablative radiation and chemotherapy preceding
transplantation.But most older refractory patients cannot
tolerate myeloablative conditioning regimens,and non-
myeloablative conditioning – a less rigorous and incomplete
form of myeloablation – is futile in patients with active
disease.These patients are out of reasonable options
outside of palliative care.
The toxicity of myeloablative conditioning,which severely
limits candidates for potentially curative HSCT,arises from
the indiscriminate exposure of healthy cells to chemotherapy
and non-targeted radiation.
Conjugates of monoclonal antibodies (mAbs) and cytotoxic
radionuclides or chemical agents have shown promise in
targeting diseased cells while sparing healthy tissues.
Iomab-B (131
I-BC8) – now under development by Actinium
for combination with non-myeloablative conditioning prior
to HSCT – is one such agent.
Acute myeloid leukaemia (AML) is a disorder of
haematopoietic progenitor cells and the most common
malignant myeloid disorder in adults (1).Some 21,000 cases
are diagnosed annually in the US,causing around 10,500
deaths.The average age on diagnosis is 67 years (2).
AML patients who fail one or more courses of chemotherapy
are termed refractory.Precise statistics for patients in this
category are difficult to come by because some respond well
to second-line therapies.To provide some perspective,as many
as 70% of older patients and up to half of younger adults with
AML fail first-line induction therapy (3),while many complete
responders eventually relapse and become refractory to
subsequent treatments.
Patient Options
Haematopoietic stem cell transplantation (HSCT) is an
option for younger refractory patients who can tolerate
Dragan Cicic and
David Gould at Actinium
Pharmaceuticals
Image:©sciencephoto–Fotolia.com

2. www.samedanltd.com l ICT 25
Pivotal Trial Design
A multi-centre,open-label,randomised,controlled,two-
arm,one-way crossover pivotal Phase 3 study of Iomab-B
is currently being prepared.It involves subjects older than
55 years with active,relapsed or refractory acute AML –
defined as either primary induction failure after two or more
cycles of chemotherapy,first early relapse after a remission
lasting less than six months,relapse refractory to salvage
chemotherapy,or second or subsequent relapse (4).
The primary efficacy objective is to demonstrate the
efficacy of Iomab-B with a protocol-specified allogeneic
HSCT versus conventional care (which is the investigator’s
choice of salvage chemotherapy induction,followed by
maintenance,consolidation,allogeneic HSCT,or any other
therapy).The primary efficacy endpoint for the study
is durable complete remission (dCR) of six months;
the secondary objective is overall survival beyond a
one-year period following treatment with Iomab-B
versus conventional care.
Before randomisation,subjects will undergo screening
that includes identification of an appropriate allogeneic
haematopoietic stem cell donor.Qualified subjects will
be randomised (1:1 ratio) to receive either Iomab-B or
conventional care,generally chemotherapy.
Therapeutic Infusions
In the Iomab-B treatment group,subjects will have a
biodistribution study (dosimetric infusion) to identify
the appropriate therapeutic infusion dose,which will be
individualised for each person,and receive the Iomab-B
therapeutic infusion in a dose administered six to 14 days
afterwards.They will then be given fludarabine and initiate
immunosuppression with cyclosporine or tacrolimus.
Next, all subjects will undergo low dose total body
irradiation,followed by infusion of the HSCT donor cells,
and be evaluated for initial response at days 28 and 56.
In the conventional care treatment control group,subjects
will be assigned to the investigator’s choice of best available
salvage chemotherapy regimen.Response monitoring will
occur on any day between day 28 to day 42,after the first
dose of salvage induction chemotherapy.
Those in the control group who achieve a complete response
will have consolidation therapy,maintenance therapy,other
best supportive care, and either myeloablative or non-
myeloablative conditioning,followed by allogeneic HSCT.
Subjects who do not manage a complete response by day
42 miss the primary endpoint but may crossover (for ethical
reasons) to the Iomab-B regimen,provided they still meet
inclusion/exclusion criteria for the trial,and may receive
chemotherapy,supportive care or other investigational
treatments.
mAb Target
Immunoconjugation therapies comprise a recognition
component attached to a cytotoxic agent. Iomab-B consists
of a mAb that targets CD45 – an antigen expressed at up
to 200,000 copies per leukocyte but which are absent on
non-haematopoietic cells. Attached chemically to the BC8
antibody is iodine 131 (131
I), a radioisotope which emits
primarily beta radiation that penetrates the target cells
and their immediate surrounding, yet does not travel more
than a millimetre inside the body. Circulating half-life
for the antibody is 68 hours; the isotopic half-life of 131
I is
eight days. Excretion of the mAb-isotope conjugate occurs
primarily through the kidneys.
By reducing overall body exposure to myeloablative
agents while targeting cells that give rise to AML, Iomab-B
could significantly increase the number of refractory adult
patients eligible for curative HSCT regimens.That was the
idea behind Iomab-B and related treatments; however, the
potential pitfalls in designing a clinical trial to demonstrate
the therapeutic benefits of Iomab-B were substantial.
Phase 2 or 3?
Standard of care becomes the first consideration when
designing a pivotal clinical trial for refractory cancer
patients.Where none exists due to the nature of the illness
or patient health status,'conventional care' becomes the
fallback option.Here lies the first challenge for designing
such trials.
The choice between a Phase 2 or Phase 3 design raises
additional scientific,medical and business issues to address.
In Phase 3 trials,patients are randomised to treatment and
control arms,whereas regulators permit pivotal Phase 2
designs to rely on historical controls.Both designs are
available for studies in refractory patients,but not for
newly diagnosed patients because therapies for treatment-
naïve patients cannot be approved solely on the basis of
historical controls.
Without the requirement for randomisation,Phase 2
trials are simpler,less expensive,of shorter duration,and
require fewer patients.However,historical control data is
quite variable,with response rates and survival differing
considerably among studies.Seemingly minor differences
in patients’general condition,mobility and socioeconomic
status can skew results significantly.Since regulators tend
to err on the side of caution, they are likely to question
historical controls cherry-picked for poor outcomes
that provide a favourable control group. Similarly, if
recruited study group patients happen to over-represent
characteristics associated with poor outcomes,the drug
sponsor faces real problems.For these reasons,and with
the knowledge that the FDA prefers randomised trials,
this approval route was pursued for Iomab-B.

3. About the authors
26 ICT l www.samedanltd.com
Participants who achieve initial complete response with no
evidence of subsequent relapse will be evaluated 180 days
later to assess dCR.All subjects will be evaluated for relapse,
adverse events and survival.Those receiving HSCT will also
be evaluated for graft rejection,as well as lymphoid and
myeloid chimerism.
Control Group Concerns
A Phase 3 design in refractory cancer patients comes
with unique concerns of which control group treatment is
primary.Ethics preclude randomising one group to a study
arm where they are almost certain to do very poorly,relative
to the other group.
Aveo Pharmaceuticals’experience with the approval of its
tivozanib kidney cancer treatment is illustrative.The FDA
did not approve the drug for sale due to concerns over the
Phase 3 design.Because 88% of study participants were from
Eastern Europe,regulators asserted that the standard of care
applied to the control group – which,in the US,includes a
comparator drug,sorafenib,not widely available in Eastern
Europe – was inferior to standard treatment in the US.
Perhaps as relevant was the study’s crossover accommodation
for standard of care control patients who did not improve on
sorafenib.While crossover was not permitted for study arm
patients,more than half of the control group participants
crossed over.When the statistics were tallied,individuals
who began in the control arm experienced slightly longer
progression-free survival – the primary clinical endpoint –
than study group subjects.
Iomab-B Strategy
The FDA found Aveo’s results“confounding”and the advisory
panel voted 13-1 against approval.The company's difficult
lesson,after spending seven years developing tivozanib,raised
abundant red flags regarding how best to proceed with the
Iomab-B development strategy.
For a start,in the absence of a standard of care,it was
decided to leave the question of conventional care to the
participating physicians.This eliminated regulatory concerns
over biases introduced through serendipity,or through the
selection of a single or limited treatment for control subjects.
Control patients would enjoy the potential benefit of
treatments selected by themselves and their physicians.
In addition,to avoid the questions of availability and patterns
of care in different countries,the trial has been limited to
the US only.
These approaches still left room for questioning the
equipoise of the trial,as the earlier results of Iomab-B were
so superior to conventional care that it might be unethical
to randomise patients to a non-Iomab-B treatment likely
to be inferior.To ensure equipoise,a one-way crossover
option was introduced that provides all patients with the
opportunity to receive Iomab-B.As explained,if a control
group treatment does not work,patients can then crossover
to Iomab-B.
Avoiding the Traps
Because this pivotal trial would include randomisation and
crossover,it was necessary to avoid the primary endpoint trap
that ensnared Aveo.The primary endpoint was defined as dCR,
with survival as a secondary endpoint.dCR was defined as
achieving a morphologic complete response lasting 180 days
or longer.Because a dCR is a binary event – it either occurs or
it does not – there was no confusion over which patients met
primary endpoint criteria,including control subjects who
crossed over.
In the world of clinical research,it seemed at one point,
with globalisation and the capability to define and
characterise subpopulations of cancer patients on the
molecular genetics level,that pivotal trials would become
quicker,simpler and less costly to run.However,these new
capabilities carry their own potential pitfalls,and with them
the need to carefully calibrate and address risks through
novel trial designs.
References
1. Estey E et al, Acute myeloid leukaemia, The Lancet 368(9550):
pp1,894-1,907, 2006
2. American Cancer Society. Visit: http://bit.ly/1Ay8nYZ
3. Luger SM and Managan JK, Salvage therapy for relapsed or refractory
acute myeloid leukemia, Ther Adv Hem 2(2): pp73-82, 2011
4. Schmid C et al, Long-term survival in refractory acute myeloid
leukemia after sequential treatment with chemotherapy and reduced-
intensity conditioning for allogeneic stem cell transplantation,
Blood 108(3): pp1,092-1,099, 2006
Dragan Cicic is the Chief Medical
Officer of Actinium Pharmaceuticals, Inc.
He joined the company in 2005 and
previously held the position of Medical
Director. Prior to this, Dragan worked as
Project Director at QED Technologies Inc.
He graduated as a Medical Doctor from
the School of Medicine at Belgrade University, and gained
his MBA from the Wharton School at the University
of Pennsylvania. Dragan was also a Nieman Fellow at
Harvard University.
David Gould is Senior Vice-President of
Finance and Corporate Development
at Actinium Pharmaceuticals, Inc.
He has 14 years of healthcare sector
investment experience across the life
sciences spectrum, most recently
at Merlin Nexus. David was also a
Vice-President at Dresdner Kleinwort Capital. He
received an MD from Jefferson Medical College at
Thomas Jefferson University, as well as gaining an
MBA in Finance from Stern School of Business, New
York University, and a BS in Molecular Biology from the
University of Wisconsin – Madison.
Email: iomab@actiniumpharma.com