An open-label, multicenter, Phase 1/2 study of radium-223 dichloride in combination with pembrolizumab in participants with stage IV non-small cell lung cancer

NSCLC remains the most common cancer worldwide in terms of new cases (1.8
million in 2012) (Ferlay et al. 2015) as well as death cases. Common sites of
metastases are bone, lung, brain, liver, and adrenal glands. Bone metastases
are detected with an incidence of 20% to 40% during the clinical course of the
disease (Kuchuk et al. 2013). The presence of bone metastases is not only known
to represent a negative prognostic factor for patients with NSCLC (O'Connell et
al. 1986), but it also significantly affects the quality of life of patients.
Radium 223 dichloride solution for injection is a targeted alpha particle
emitting radiopharmaceutical that exhibits a dual targeting mechanism of
action: it destroys tumor cells and inhibits tumor-induced pathoabbrelogical
bone reaction. The bone targeting property of radium 223 is similar to that of
other alkaline earth elements, like calcium or strontium-89. However, the
radiation characteristics of an alpha particle emitting radionuclide appear to
be more advantageous than that of a beta emitting radionuclide. Radium 223,
with a physical half life (t*) of 11.4 days, emits high linear energy transfer
(LET) alpha radiation, with a range limited to less than 100 micrometers. The
high LET of alpha emitters (80 keV/micrometer) leads to a high frequency of
double-strand DNA breaks in adjacent cells, resulting in an antitumor effect on
bone metastases.
Radium-223 is an isotope which decays and is not metabolized by any enzyme. No
impact on radium-223 is, therefore, expected by polymorphic enzymes. Radium-223
dichloride is administered intravenously (IV); therefore, absorption related
differences are not applicable for this compound. Given these properties of
radium-223 dichloride, it is unlikely that PK interaction may occur.
Radium-223 dichloride was first approved in the EU in 2013 to treat men with
mCRPC and symptomatic bone metastases based on data from the ALSYMPCA study. In
this study radium-223 dichloride increased OS (hazard ratio [HR] 0·70,
p<0·001), reduced the risk of symptomatic skeletal events (SSEs) (HR 0·66,
p<0·001), and improved quality of life (odds ratio 1·82, p=0·004) compared with
placebo when added to best standard of care in patients with mCRPC and bone
metastases who previously had either received docetaxel or were not candidates
for docetaxel treatment (Nilsson et al. 2016, Parker et al. 2013, Parker et al.
2017). There were fewer treatment-emergent AEs with radium-223 dichloride than
with placebo (Parker et al. 2013) in ALSYMPCA, confirmed with data from
long-term FU (Parker et al. 2017).
In ERA-223 * a Phase 3, double-blind, randomized controlled trial, concurrent
treatment of abiraterone acetate plus prednisone/prednisolone (AAP) plus
radium-223 dichloride resulted in an increased fracture risk compared to AAP
alone in patients with mCRPC. At the primary analysis, treatment-emergent
fractures occurred in 103 (26%) of 392 patients in AAP plus radium-223
dichloride group and 38 (10%) of 394 patients in the AAP plus placebo group.
Most fractures were outside of sites of bone metastases in both treatment
groups. Osteoporotic fractures accounted for most of the observed differences
in fracture incidence between the study groups. Bone health agent (BHA) use at
baseline was lower in patients who experienced a fracture than in those who had
not. Concurrent treatment with AAP plus radium-223 dichloride did not improve
symptomatic skeletal event-free survival (SSE-FS) compared to treatment with
AAP plus placebo There was no statistically significant difference in OS
between the groups.
While ERA-223 demonstrates that radium-223 dichloride should not be
administered in combination with AAP, radium-223 dichloride remains a
life-prolonging treatment option for patients with bone-dominant mCRPC and
disease progression, based on robust clinical and post-marketing data. A
detailed description of the chemistry, pharmacology, efficacy, and safety of
radium-223 dichloride is provided in the investigator*s brochure (IB).

Pembrolizumab (Keytruda®) is a potent humanized immunoglobulin G4 monoclonal
antibody with high specificity of binding to the programmed cell death 1 (PD 1)
receptor, thus inhibiting its interaction with PD-L1 and PD ligand 2 (PD-L2).
Based on the preclinical in vitro data, pembrolizumab has high affinity and
potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable
preclinical safety profile and is in clinical development as an intravenous
immunotherapy for advanced malignancies. Pembrolizumab is indicated for the
treatment of patients across a number of indications. For more details on
specific indications refer to the IB.
In the first-line setting, pembrolizumab is approved for the treatment of
NSCLC, both as a single agent (for PD-L1 tumor protein score [TPS] *50%) and in
combination with cisplatin or carboplatin+pemetrexed (non squamous only,
regardless of PD-L1 TPS) as well as in combination with
carboplatin-nab-paclitaxel or carboplatin-paclitaxel (squamous NSCLC,
regardless of PD-L1 TPS). In the second line setting after failure of
platinum-based chemotherapy, single agent pembrolizumab is indicated for
treatment of NSCLC with a PD-L1 TPS *1%. There are no comprehensive data
regarding the efficacy of pembrolizumab in patients treated after progression
on an immune checkpoint inhibitor.

The purpose of the study is to determine the safety and assess the efficacy of
the combination of radium-223 dichloride and pembrolizumab in participants with
stage IV NSCLC with bone metastases who are either treatment naïve or have
progressed on prior anti programmed cell death protein (ligand) 1 (PD-L1/PD-1)
therapy.

This is an open-label, multicenter, Phase 1/2 study which includes a safety
run-in as well as two distinct cohorts to assess the efficacy of the
combination of radium-223 dichloride and pembrolizumab in participants with
NSCLC.

Phase 1
The Phase 1 part of the study will include participants with stage IV NSCLC
either treatment naïve (PD-L1 tumor protein score [TPS] * 50%) or after
progression on prior therapy with immune checkpoint inhibitors (irrespective of
PD-L1 TPS). It is designed to determine the tolerable dose of radium-223
dichloride in combination with standard dose of pembrolizumab (200 mg
pembrolizumab every 3 weeks for a maximum of 35 cycles). Participants enrolled
in the Phase 1 part of the study will receive the starting dose of 55 kilo
Becquerel (kBq)/kg body weight of radium-223 dichloride which is the approved
monotherapy dose for metastatic Castration Resistant Prostate Cancer (mCRPC).
Radium-223 dichloride will be administered every 6 weeks for up to 6
administrations. All participants will be evaluated for occurrence of DLTs
during the DLT observation window (6 weeks after first dose of pembrolizumab).
In case of DLTs, the radium-223 dichloride dose may be reduced by one dose
level to 33 kBq/kg body weight (see Section 4.1.2.1).

Phase 2
The main purpose of the Phase 2 part of the study is to evaluate the efficacy
of the combination of radium-223 dichloride and pembrolizumab. The Phase 2
includes 2 distinct cohorts. In Cohort 1 participants with treatment naïve
stage IV NSCLC (PD-L1 TPS * 50%) will be randomized 1:1 to receive either
radium-223 dichloride plus pembrolizumab or pembrolizumab monotherapy. In
Cohort 2 (single arm) participants with stage IV NSCLC who have progressed on
prior therapy with immune checkpoint inhibitors (irrespective of PD-L1 TPS)
will receive radium-223 dichloride plus pembrolizumab. Radium-223 dichloride
will be administered every 6 weeks at the RP2D as determined in the Phase 1
part (for a total of up to 6 administrations). Pembrolizumab 200 mg will be
administered every 3 weeks for a maximum of 35 cycles.

Pembrolizumab will be administered every 3 weeks for up to 35 cycles or until
progressive disease (PD), death, or withdrawal of consent (whichever occurs
first). Radium-223 dichloride will be administered every other cycle of
pembrolizumab (every 6 weeks) for a total of up to 6 administrations or until
PD, death, or withdrawal of consent (whichever occurs first).

The study medication may improve the medical condition of the patient, but this
is not certain.
The information collected in this study will help the study sponsor and doctors
learn more about the study drug. This information may help future patients.


Disadvantages of participation in the study may be
- possible side effects/complications of the study medication
- possible side effects/discomforts of the evaluations in the study
- You might need to stop taking other medicines

Participation in the study also means:
- additional time;
- additional or longer hospital stays;
- additional tests;
- instructions you need to follow;

The participation of the patient will last about 12 months.
However, this may be longer based on how well the patient respond to the
treatment.