Primary Objectives:- To compare ORR (objective response rate) using RECIST 1.1 for NKTR-214 combined with nivolumab and that of nivolumab monotherapy in participants with previously untreated unresectable or metastatic melanoma- To compare PFS (…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The efficacy endpoints of ORR, PFS and OS were assessed by a BICR.
The addition of bempegaldesleukin to nivolumab did not result in a
statistically significant improvement in PFS (HR 1.09, 97% CI, 0.88-1.35) or
ORR compared to nivolumab monotherapy as assessed by Blinded Independent
Central Review (BICR), and the significance threshold for OS
was also not crossed at the combined first and second OS analyses.
Furthermore, there was added toxicity with bempegaldesleukin plus nivolumab
compared to nivolumab monotherapy including NK a higher incidence of
drug-related adverse events (AEs), drug-related serious adverse events (SAEs)
and drug-related AEs leading to study treatment discontinuation.
Secondary outcome
Further efficacy endpoints will be assessed by BICR and the investigator and in
correlation with biomarker analysis.
Safety and tolerability will be assessed by review of Incidence of adverse
events, serious adverse events, and select adverse events.
Per Protocol Amendment 03, the secondary and exploratory objectives except
biomarker parameters are no longer applicable. Biomarker sample collection will
not be applicable per Protocol Amendment 03. However, exploratory analysis of
biomarkers on previously collected specimens may be conducted.
Background summary
PD-1 blockade is the recommended first-line therapy for treatment of BRAF WT
and BRAF Mutant unresectable or metastatic melanoma in the National
Comprehensive Cancer Network (NCCN) Guidelines.
Although first-line treatment with checkpoint inhibitors significantly improved
clinical outcome for melanoma patients, a significant portion of patients
progress or discontinue treatment due to treatment-related toxicities. These
data support the need for combinations such as NKTR-214 and nivolumab that may
yield greater clinical efficacy without adding significant treatment related
toxicities.
The PIVOT-02 study of nivolumab and NKTR-214 included an expansion cohort in
patients with treatment-naive melanoma. Previous analysis of the dose
escalation part showed the response rate in this cohort was 69% (11 out of 16
participants) with 1 complete response and 10 partial responses with all
responders maintaining their response. With 3 years of follow-up, nivolumab
monotherapy in the Checkmate 067 study demonstrated an ORR of 44%, a 3-year PFS
of 32% and a 3-year OS of 52%.13 The 3-year analysis of Checkmate 067
reaffirmed that responses to checkpoint inhibitors continue to evolve with
longer follow-up as the number of participants achieving a complete response to
nivolumab increased from 28 to 52 patients out of 316 total (9% to 16%) with a
median duration of response that has still not been reached. It was anticipated
that a similar evolution of responses would be seen in the combination of
NKTR-214 and nivolumab as evolution of responses over time has been reported in
the setting of high dose IL-2.
CA045001 was a Phase 3 randomized study of NKTR-214 combined with nivolumab vs
Nivolumab monotherapy in participants with unresectable or metastatic melanoma
that is previously untreated.
Study data were recently analyzed as planned and showed that the combination of
bempegaldesleukin with nivolumab did not add benefit but could add side
effects. Because of this, participant on Arm A and receiving bempegaldesleukin
and nivolumab, will stop bempegaldesleukin and continue nivolumab alone.
Participants on arm B can continue receiving nivolumab alone.
The study remains open so that participants can recieve nivolumab alone. Blood
and urine samples will be taken before each treatment to assess how
participants are responding to the treatment.
Study objective
Primary Objectives:
- To compare ORR (objective response rate) using RECIST 1.1 for NKTR-214
combined with nivolumab and that of nivolumab monotherapy in participants with
previously untreated unresectable or metastatic melanoma
- To compare PFS (progression free survival) using RECIST 1.1 of NKTR-214
combined with nivolumab and that of nivolumab monotherapy in participants with
previously untreated unresectable or metastatic melanoma
Secondary Objectives:
- To evaluate efficacy of NKTR-214 combined with nivolumab and that of
nivolumab monotherapy
- To evaluate the association between PD-L1 tumor expression on tumor cells (>=
1% or < 1%/indeterminate) and efficacy measures including PFS and ORR by
blinded independent committee for radiology (BICR) and OS.
- To evaluate the safety and tolerability of NKTR 214 combined with nivolumab
and that of nivolumab monotherapy
Exploratory Objectives:
- To characterise the pharmacokinetics of NKTR-214 combined with nivolumab and
that of nivolumab monotherapy
- To characterise the immunogenicity of NKTR-214 combined with nivolumab and
that of nivolumab monotherapy
- To assess the effect of NKTR-214 combined with nivolumab and that of
nivolumab monotherapy on quality of life
- To assess the effect of NKTR-214 combined with nivolumab and that of
nivolumab monotherapy on tumor and blood based biomarkers
Per Protocol Amendment 03, the secondary and exploratory objectives except
biomarker parameters are no longer applicable. Biomarker sample collection will
not be applicable per Protocol Amendment 03. However, exploratory analysis of
biomarkers on previously collected specimens may be conducted.
Study design
This study was an open-label, phase 3 trial that aimed to assess the impact on
response rate and overall survival in patients treated with nivolumab in
combination with NKTR-214 when compared to patients treated with monotherapy
nivolumab in subjects, with no prior systemic anticancer therapy given as
primary therapy for advanced or metastatic melanoma.
783 patients were treated globally.
Participants received either nivolumab (360 mg) combined with NKTR-214 (0.006
mg/kg) or Nivolumab alone as an iv infusion every 3 weeks until disease
progression, unacceptable toxicity, withdrawal of consent, the study ends or a
maximum treatment duration of 2 years, whichever occurs first. After treatment,
all subjects entered the follow-up phase of the study. Subjects had 2 visits
within the first 100 days after stopping treatment. Remaining follow-up visits
occured very 3 months and could be conducted over the phone.
Participants were permitted to continue on NKTR-214 +/- nivolumab beyond
initial defined progression, as long as they met the protocol criteria.
Following analysis that showed the addition of bempegaldesleukin to nivolumab
did not result in a statistically significant improvement in progression free
survival or overall survival rate compared to nivolumab monotherapy and added
toxicity, protocol amendment 3 will be implemented to allow participants who
are currently receiving bempegaldesleukin plus nivolumab to discontinue
bempegaldesleukin and continue nivolumab monotherapy. All participants will
receive nivolumab monotherapy at 480 mg IV once every 4 weeks. Participants <
40 kg will be administered a body weight adjusted nivolumab dose of 6 mg/kg IV
once every 4 weeks. Study treatment will be until disease progression,
unacceptable toxicity, withdrawal of consent, the study ends or a maximum
treatment duration of 2 years, whichever occurs first. After completing
treatment patients will be followed for 100 days then study participation ends
unless they have side effects that require further follow up.
Intervention
Subjects received open-label treatment with nivolumab (flat dose 360 mg every 3
weeks) in combination with NKTR-214 (0.006 mg/kg every 3 weeks) or Nivolumab
monotherpy (flat dose 360 mg every 3 weeks). Both nivolumab and NKTR-214 are
provided by the sponsor.
Following analysis that showed the addition of bempegaldesleukin to nivolumab
did not result in a statistically significant improvement in progression free
survival or overall survival rate compared to nivolumab monotherapy and added
toxicity, protocol amendment 3 will be implemented to allow participants who
are currently receiving bempegaldesleukin plus nivolumab to discontinue
bempegaldesleukin and continue nivolumab monotherapy. All participants will
receive nivolumab monotherapy at 480 mg IV once every 4 weeks. Participants <
40 kg will be administered a body weight adjusted nivolumab dose of 6 mg/kg IV
once very 4 weeks.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential), and monitoring for adverse events. If there is no archive
tumour tissue available or the sample was taken too long ago (more than 3
months), patients will be required to have a biopsy in order to participate. In
addition, every 9 weeks until week 52 and then every 12 weeks, patients will
undergo radiographic assessment of their tumors (by CT or MRI) until disease
progression or treatment discontinuation whichever occurs later. Blood will
also be collected at certain visits for research purposes (PK, immunogenicity
and biomarker studies) as well as optional stool samples for microbiome
analysis. The frequency of visits and number of procedures carried out during
this trial would typically be considered over and above standard of care. These
procedures are conducted by medically trained professionals and every effort
will be made to minimise any risks or discomfort to the patient.
Upon implementation of protocol amendment 3: Nivolumab treatment will be every
4 weeks until unacceptable toxicity, withdrawal of consent, the study ends or a
maximum treatment duration of 2 years, whichever occurs first. After completing
treatment patients will be followed for 100 days then study participation ends
unless they have side effects that require further follow up.
Patients will undergo physical examinations, weight and vital sign
measurements, blood and urine tests for safety assessment and to asses response
to treatment, pregnancy testing (for females of child bearing potential),
review of medications and monitoring for adverse events. Scans will be
performed per standard of care.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
a) Participants must have an Eastern Cooperative Oncology Group (ECOG)
performance status of <= 1 (adults 18 years or older) or/Lansky Performance
Score >= 80% (for minors (ages 12-17 only)
b) Histologically confirmed stage III (unresectable) or stage IV melanoma, as
per American Joint Committee on Cancer (AJCC) staging system, 8th edition
c) Treatment-naïve participants (ie, no prior systemic anticancer therapy for
unresectable or metastatic melanoma) with the exception of prior adjuvant
treatment for melanoma with approved agents (eg, BRAF/MEK inhibitors,
ipilimumab, nivolumab, pembrolizumab or interferon). Participants who have had
a recurrence within the 6 months of completing adjuvant treatment are not
eligible.
d) Measurable disease by computed tomography (CT) or magnetic resonance imaging
(MRI) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria
e) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained
tumor tissue sections, obtained within 3 months prior to enrollment, with an
associated pathology report, must be submitted to the core laboratory for
inclusion. FFPE tissue block and unstained slides submitted should be from
biopsy obtained within 6 months prior to enrollment. Unstained slides should be
sectioned within 3 months prior to submission.
i) To be randomized, a participant must be classified as PD-L1 positive (>=
% tumor cell membrane staining) vs PD-L1 negative (< 1% tumor cell membrane
staining)/PD-L1 indeterminate (tumor cell membrane scoring hampered by high
cytoplasmic staining or melanin content). Not evaluable participants are not
eligible for randomization.
f) Participants must have known BRAF V600 mutation status or consent to BRAF
V600 mutation testing per local institutional standards by approved methodology
during the Screening period.
Exclusion criteria
a) Active brain metastases or leptomeningeal metastases. Participants with
brain metastases are eligible if these have been treated and there is no MRI
evidence of progression for at least 8 weeks after treatment is complete and
within 28 days prior to first dose of study treatment administration.
b) There must also be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior
to study treatment administration. Stable dose of anticonvulsants is allowed.
c) Patient who received whole brain radiation therapy are not eligible.
d) Uveal melanoma is excluded.
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001423-40-NL |
| ClinicalTrials.gov | NCT03635983 |
| CCMO | NL67164.091.18 |