Evaluating the safety of shortened infusion times for different oncological immunotherapies; An observational prospective study

immunotherapy mAbs are highly effective, but can also cause infusion related
hypersensitivity reactions. The occurrence of these reactions varies greatly
between mAbs. Combination therapy with other drugs does influence the
probability of an infusion reaction during a cycle. Most mAbs show a decrease
in the incidence of IRRs but some mAbs show an increase in the incidence of
IRRs in subsequent administrations. A higher infusion rate is associated with a
higher likelihood for a reaction. Infusion related reactions are specified
using the definition of Common Terminology Criteria for Adverse Events (CTCAE)
criteria for: infusion related reaction. An infusion reaction usually starts
within 30 to 120 minutes after start of administration.

The mechanism of the infusion related reactions is not concentration dependent,
but mostly cause by cytokine release, caused by binding of the mAb to the
target cell. in this way cytokines are released into the circulation causing
symptoms.

Several measures can be taken to manage the infusion related reactions, such as
a gradual increase of the dosage over the course of treatment, tapering the
infusion time (for example 90-60-30 minutes), or using pre-treatment with
antihistamines and corticosteroids. Due to the possibility of hypersensitivity
reactions, all mAbs have restrictions on their rate of infusion, mostly
determined during registration trials. However, it is known from earlier
research, and pharmacologically expected, that infusion times can be shortened.
For example, bevacizumab in 10 minutes had comparable incidence of IRRs to
bevacizumab in 30 minutes

Based on this information we expect that mAbs can be infused in a shorter time
(to around 10 -15 minutes per mAb% of the current infusion time). The
advantages are the shorter hospital visits for patients, cost-effective home
treatment and of course the amount of time saved for patients and nurses and
finally increased capacity on the day-care facility. In Gil et al.5 a
shortening of the infusion time to 10 minutes for Bevacizumab alone for just 73
patients created ¤17.960,30 nursing capacity per year. The waiting list for the
Daycare Hospital Oncology Unit where these infusions were performed was also
decreased. therefore the capacity of these facilities could be significantly
improved.

It is suggested that mAbs are dosed on the top of their dose response curve¬38.
This would explain why it is hard to establish a PK-PD relationship. As these
drugs are structurally *over* dosed it would be possible to adapt different
strategies to optimize dosing. The dosing of many monoclonal antibodies is
currently based on a fixed dosing scheme, mostly based on Body Surface Area
(BSA). Optimized dosing could potentially decrease the amount infusions with
the monoclonal antibodies, thereby decreasing the (high!) costs of the
treatment significantly. Another point is that is the stretching of the dosing
intervals. As the extension of these dose intervals could lead to optimization
of the patient*s time spend in the hospital for infusion, thus improving the
quality of life. This would lead to a decrease of the burden for the oncology
day care facility in Isala as well.

This study has been transitioned to CTIS with ID 2024-518878-14-01 check the CTIS register for the current data.

Primary Objective
To determine the incidence and grading of infusion related/hypersensitivity
reactions reported per drug using the definition of Common Terminology Criteria
for Adverse Events (CTCAE) criteria for: infusion related reaction during
accelerated infusion of mAbs, compared to historical matching cohorts.

Secondary objectives
• To evaluate the intra- and inter-individual variation in plasma levels of the
studied mAbs.
• Patient reported experience measures on the shortened infusion times.
• Health economic evaluation of the intervention

This study is an observational, explorative, prospective study to show whether
shortening of infusion times for patients using nivolumab, pembrolizumab,
trastuzumab, ipilimumab, durvalumab, atezolizumab continues to be associated
with an acceptable safety profile.
The observational prospective study analysis from the medical records of
demographics, anticancer drug use, adverse events and laboratory parameters are
collected until end of treatment, death, or present time for patients.

The study is designed in two parts. In Part A, nivolumab, ipilimumab and
pembrolizumab will be studied in three drug specific cohorts. Each drug
specific cohort consists of a Run-In group involving 10 subjects and an
Extension group of additional 82 subjects. In total 97 subjects will be
included in each drug specific cohort. A total of 15 patients will be included,
to account for fall out . For instance, due to disease progression.

Safety evaluations will be performed at least after completion of each Run In
group (n=10). The evaluations will be performed by an independent institutional
safety board.
Each extension group may only start after approval of the institutional safety
board.

In Part B, 4 additional drugs will be studied in 4 drug specific cohorts,
provided no serious adverse effects have occurred in part A, defined as no more
than 2 subjects experienced infusion related reaction of grade 2 or higher. The
selected drugs are bevacizumab, trastuzumab, durvalumab and atezolizumab.
As in part A, in part B each drug specific cohort also consists of a Run-In
group involving 10 subjects and an Extension group of additional 82 subjects.
In total 97 subjects will be included in each drug specific cohort. Again, 15
patients will be included, to account for fall out.

Study procedure per patient
Patients start with standard of care. Standard of care is 100% of the infusion
time as recommended by the SMPC. The aim of this period is to identify patients
that develop IRRs and to prevent them from continuing onto the intervention
procedure. Patients may continue, if during standard of care no IRR of grade 2
or higher has occurred. Before continuing to the intervention period of the
study we evaluate the safety, as during the intervention period the infusion
times will be shortened according to table 9.
During the intervention period the infusion times will be shortened as stated
in table 9. During every cycle the SMPC infusion time is reduced with 50%,
until a minimum infusion time of 10 minutes. If patients experience IRR during
the intervention part they will be treated for the IRR per protocol and
excluded from the study.

All patients are 30 minutes observed after completion of the infusion during
the complete course of the study.

For assessment of the pharmacokinetics of the different mAbs, through blood
samples will be collected during cycle 2 to 4. Samples will be taken before the
start of the next infusion. The Cmax samples will be taken during one of the
cycles. One extra venapuncture is nessecary.
In the Run-In cohorts (n=10) during one cycle (preferably cycle 2) an
additional blood sample will be collected after infusion to determine Cmax
levels and clearance of each drug. No additional sampling will be performed
during the other cycles.
Bioanalyses will be performed by a validated method in the laboratory of the
pharmacy of the LUMC.

The risk-benefit analysis:
The possible risks of this study are additional blood sampling and infusion
reaction that might occur due to fastened Immunotherapy cycles. The chance of
excessive damage is nihil therefore it is considered a low-risk study as IRR on
normal therapy is low and patients prone to IRR are not included in the study.
The blood samples taken prior to infusion are not to be an excessive burden
since no extra venepuncture is necessary. Foradditional blood sample will be
collected after infusion to determine Cmax levels and clearance of each drug.
An extra venepuncture is necessary to obtain these blood samples. These are not
to be an excessive burden.

Group relatedness:
The group of patients receiving oncological immunotherapy are related to this
study.