Improving peptide receptor radionuclide therapy with poly ADP ribose polymerase inhibitor.

Neuroendocrine tumors (NETs) are well-differentiated cancers that originate
from the sensory and secretory neuroendocrine cells, predominantly located in
the bronchopulmonary and gastrointestinal tracts. The rarity and heterogeneity
of NET disease has hampered drug development and clinical trials in this field.
Consequently, patients presenting with advanced stages of NET have a limited
prognosis as systemic treatment options are limited.
Peptide receptor radionuclide therapy (PRRT) with
177Lutetium-DOTA-Tyr3,octreotate (177Lu-DOTATATE) is an effective treatment for
patients with locally advanced or metastatic NETs.
A large multicenter phase III trial (NETTER-1)using the Rotterdam protocol was
successfully completed. Patients randomized to PRRT with 4 cycles of
177Lu-DOTATATE displayed a significantly improved progression-free survival of
28 months compared to 8 months in the control arm. The risk of progression or
death was 79% lower in patients treated with PRRT and quality of life was
improved. However, partial and complete response rates after PRRT are limited
at 17% and 1% of patients, respectively, and disease progression occurs after
approximately 2.5 years. Therefore, adaptations of the therapeutic regimen of
PRRT are urgently needed. As administering a higher PRRT dose will lead to
radiation-induced side effects in healthy tissues, especially the bone marrow
and kidneys, many groups have focused on other targeted therapeutic strategies
capable to stimulating tumor cell death.
Following our preclinical work on molecular mechanisms of the DNA damage
response to radiation, we aim to overcome the current limitations of PRRT by
enlarging the therapeutic window. During PRRT of NETs, therapeutic
radionuclides are coupled to peptides (177Lu-DOTATATE) that can specifically
bind to the somatostatin receptors (SSTs) overexpressed on the tumor surface.
The β-particle radiation emitted by 177Lu-DOTATATE induces both single-strand
breaks (SSBs) and double-strand breaks (DSBs) in the tumor cell*s DNA. While a
certain amount of DNA damage can be repaired, a higher level will induce cell
death. In order to force more cancer cells to reach the lethal threshold, we
will prevent repair of PRRT-induced DNA damage using the PARP-1 inhibitor
(PARPi) olaparib. PARP-1 is essential for SSB repair and when SSBs are not
repaired, they will be converted into DSBs during cell division. The
combination of PRRT with olaparib can potentially increase the rate at which
the tumor cells accumulate PRRT-induced DSBs and thereby increase the tumor
cell death rate.
Furthermore, ongoing studies in xenografted mice show a significant decrease in
tumor size in mice treated with PRRT and olaparib compared to PRRT alone as
well as a delay in tumor regrowth (Figure 2). Excitingly, we have reached 13%
completed response in the PRRT and olaparib combination group while none of the
mice treated with PRRT alone were cured. Olaparib alone did not influence tumor
growth and no acute toxicity was observed in the mice.
Together, these clinical data provide sufficient justification to pursue
clinical development of a combination of a PARP inhibitor with PRRT.

This study has been transitioned to CTIS with ID 2024-513007-14-00 check the CTIS register for the current data.

The current trial aims to asses the safety of this combination in a phase I
trial with olaparib dose escalation during two cycles of 177Lu-DOTATATE in
salvage setting in patients with advanced GEP NET, progressive after initial
PRRT.

This is a phase I dose-escalation, single arm, prospective study among patients
with advanced NETs that have progressive disease according to RECIST v1.1
following initial or salvage PRRT. The study will be initiated at Erasmus MC,
but based upon recruitment and interest additional centers may be added after
approval of a submitted amendment.
Patients eligible for salvage PRRT will receive 18 days of olaparib starting 3
days before PRRT until 14 days after. Patients will receive a fixed standard
dose of salvage PRRT, consisting of 2 cycles of 7.4 GBq 177Lu-DOTATATE. Four
dose tiers of olaparib will be evaluated in a dose escalation sequence next to
the two cycles of PRRT according to the following regime:
- 100 mg q.d.
- 100 mg b.i.d.
- 200 mg b.i.d.
- 300 mg b.i.d.
Patients discussed at the multidisciplinary team and accepted for salvage PRRT
will be approached for participation if they fulfil the inclusion and exclusion
criteria.

Study design is a classic 3+3 dose escalation with 3 patients per dose tier.
The 3+3 design with fixed doses per patient and opening of a higher dose tier
after complete evaluation of all safety data until day 57 was chosen because of
the sub-acute toxicity observed after PRRT. A dose tier will open for 3
patients. In case no dose-limiting toxicity (DLT) is observed in the first
cycle of PRRT, successive participants will escalate the olaparib dose to the
next tier.
In case of the occurrence of 1 DLT, inclusion of up to 3 additional patients at
the same dose is pursued, after which dose escalation can follow if no
additional DLT is observed. In case of >=2/3 or >=2/6 DLTs at a given dose level,
further dose escalation will be stopped and an additional 3 patients will be
treated at the previous dose level. In case of unexpected toxicity (>=2/3 or
>=2/6 DLTs) at the starting dose of 100mg q.d., a single de-escalation step to
50 mg q.d. is allowed.
The maximum tolerated dose of olaparib is the highest dose level at which 0 or
1 DLTs are encountered in 6 patients.

2x18 days taking tablets of olaparib, 2 biopsies of the tumor, 29 additional
venipunctures, 7 ECG*s, 4 additional SPECT/CT scans.

PRRT with 177Lu-DOTATATE and olaparib are treatments which are already used in
therapy for cancer and of which the side-effects are known. However, the
effects and side-effects of this combination are still unknown, therefore this
phase 1 dose-escalation study is necessary. The patients receive de PRRT as
known and have to take tablets of olaparib for 18 days in addition. They will
be checked frequently for effects and side-effects of this combination therapy
to reduce the risk as much as possible.
It is necessary to draw blood to determine the toxicity and take biopsies to
evaluate the effect on the tumor cells.
There will be drawn approximately 350 ml of blood in total.