24 ICT l August 2015

Fail SafeA 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 (131I-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

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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 –

defi ned as either primary induction failure after two or more

cycles of chemotherapy, fi rst early relapse after a remission

lasting less than six months, relapse refractory to salvage

chemotherapy, or second or subsequent relapse (4).

The primary effi cacy objective is to demonstrate the

effi cacy of Iomab-B with a protocol-specifi ed 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 effi cacy 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 identifi cation of an appropriate allogeneic

haematopoietic stem cell donor. Qualifi ed 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 fl udarabine 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 fi rst

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 (131I), 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 131I 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 signifi cantly 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 benefi ts of Iomab-B were substantial.

Phase 2 or 3?

Standard of care becomes the fi rst 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 fi rst challenge for designing

such trials.

The choice between a Phase 2 or Phase 3 design raises

additional scientifi c, 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 signifi cantly. 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.

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 diffi cult

lesson, after spending seven years developing tivozanib, raised

abundant red fl ags 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 benefi t 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 defi ned as dCR,

with survival as a secondary endpoint. dCR was defi ned 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 defi ne 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.

References1. Estey E et al, Acute myeloid leukaemia, The Lancet 368(9550):

pp1,894-1,907, 20062. American Cancer Society. Visit: http://bit.ly/1Ay8nYZ3. Luger SM and Managan JK, Salvage therapy for relapsed or refractory

acute myeloid leukemia, Ther Adv Hem 2(2): pp73-82, 20114. 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 Offi cer 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