Primary objectives:• to assess the safety of combining nivolumab, ipilimumab and up to 3 fractions of medium dose hypofractionated radiotherapy (mRT) to multiple tumor sites (1 to 4, with at least 1 site receiving 24Gy)• to explore the efficacy of…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety will be defined as (i) the percentage of patients with adverse events
(NCI CTCAE), the grade and the relationship to IPI/NIVO/mRT will be assessed.
Tumor responses will be assessed by ORR and DCR, overall and per study group.
Clinical outcome parameters such as PFS, and OS at 1 and 2 years, will be
registered.
Secondary outcome
-
Background summary
Only a minority of non-small cell lung cancer (NSCLC) patients with low or
negative tumor PD-L1 levels benefit from anti-PD-1 therapy. We hypothesized
that the combination of ipilimumab, nivolumab and medium dose radiotherapy
using 3x8Gy (IPI/NIVO/mRT) will act synergistically by enhancing immune
activation, thereby leading to better tumor control. In this study, we aim to
prove that in patients with low and negative PD-L1 tumors following progression
on first line chemotherapy-pembrolizumab, treatment with IPI/NIVO/mRT is safe,
and that it could elicit tumor responses, and eventually improve disease free
and overall survival.
Study objective
Primary objectives:
• to assess the safety of combining nivolumab, ipilimumab and up to 3 fractions
of medium dose hypofractionated radiotherapy (mRT) to multiple tumor sites (1
to 4, with at least 1 site receiving 24Gy)
• to explore the efficacy of combining IPI/NIVO/mRT in terms of objective
response rates (ORR) and disease control rates (DCR) (short term)
Secondary objectives:
• To evaluate the ORR and DCR differences between tumors with a low PD-L1 and
with negative PD-L1 expression after IPI/NIVO/mRT
• To evaluate the effects of IPI/NIVO/mRT on PFS and OS (long term)
Study design
a single center, single arm, phase 1 / 2 trial. This will be a 2-stage study;
in stage-1, a total of 22 patients in each of the 2 defined groups will be
enrolled, and if at least 1 patient has an objective response, the study will
proceed to stage-2, in which additional patients will be recruited. A total of
30 evaluable patients are needed.
Intervention
In the first 6 weeks, all patients will undergo treatment with the combination
of ipilimumab (IPI, 1mg/kg on day 1), nivolumab (NIVO; 240mg, q2w) and
medium-dose multi-site hypofractionated radiotherapy (using 8Gy fractions on
days 8, 10 and 12). After this 6 week treatment period, and if no disease
progression is observed, patients will continue IPI (1mg/kg, q6w) and NIVO
(360mg, q3w) until disease progression or unacceptable toxicity.
Study burden and risks
The current literature lacks data on the toxicity and efficacy of this
IPI/NIVO/mRT approach. However, by extrapolating data from the first line
treatment setting in NSCLC, we expect that the burden and risks associated with
study participation will be acceptable. The combination of IPI/NIVO has
comparable treatment-related toxicity as chemotherapy in the 1st line. However,
the combination of IPI/NIVO performed much better than chemotherapy in the
first line setting, especially for PD-L1 negative tumors The safety of
combining concomitant IPI/NIVO and medium dose RT is unknown, however,
preliminary safety data on IPI/NIVO consolidation after chemoradiotherapy in
stage 3 NSCLC shows that toxicities are manageable. Clinical trials evaluating
combined immunotherapy and radiotherapy have shown encouraging results on
immunotherapy efficacy. In this trial, there is a potential immunological
synergy of combining anti-PD-1, anti-CTLA4 and medium-dose radiotherapy for
priming and activating the effector T-cells. Therefore, we expect that patients
are likely to derive clinical benefit from study participation. Furthermore,
the current routine second line therapy is docetaxel, which has a comparable
toxicity profile with a response rate of about 10%. Patients are still eligible
to receive docetaxel if they fail to respond to the IPI/NIVO/mRT. Consequently,
we do not expect enrolled patients to be *undertreated* because of study
participation. The insights obtained in the translational part of this study
can provide valuable insights for improving treatment options for future NSCLC
patients.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed NSCLC, negative for EGFR, ALK or other treatable
oncogenic drivers
2. WHO PS 0-2
3. Be willing and able to provide written informed consent for the trial.
4. Be above 18 years of age on day of signing informed consent.
5. Patients must have radiological disease progression on chemo-pembrolizumab
6. Have at least 1 lesion (up to 4) that is amenable to treatment with
radiotherapy (3x8Gy as per judgement of the radiation oncologist), and at least
1 other unirradiated lesion which can serve as a measurable lesion for
assessing tumor response based on RECIST 1.1.
7. Demonstrate adequate organ function, as deemed acceptable by the treating
physician in the context of metastatic NSCLC
Exclusion criteria
1. Patients with fast progressive disease as per judgement of the treating
physician.
2. Patients who had received any radiotherapy during previous treatment with
chemo-pembrolizumab.
3. Subjects with a condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive
medications within 14 days of day 0. Inhaled or topical steroids, and adrenal
replacement steroid >10 mg daily prednisone equivalent, are permitted in the
absence of active autoimmune disease.
4. Active autoimmune disease requiring systemic steroid treatment within the
past 3 years or a documented history of clinically severe autoimmune disease,
or a syndrome that requires systemic steroids.
5. Evidence of interstitial lung disease or active, non-infectious pneumonitis.
6. Active infection requiring systemic therapy.
7. A history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
8. Active Hepatitis B or C.
9. Psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
10. Has received prior therapy with an anti-CTLA-4 antibody, or any other
antibody or drug specifically targeting T-cell co-stimulation or immune
checkpoint pathways (except pembrolizumab).
11. Has developed immune related adverse events on immunotherapy that
necessitated stopping pembrolizumab indefinitely.
12. Patient is pregnant or breastfeeding, or expecting to conceive within the
projected duration of the trial, starting with the pre-screening or screening
visit through 23 weeks after the last dose of trial treatment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-001097-29-NL |
| CCMO | NL73485.029.20 |
| OMON | NL-OMON25166 |