This study has been transitioned to CTIS with ID 2024-511996-13-00 check the CTIS register for the current data. The primary objective is to investigate the efficacy of IO102-IO103 in combination with pembrolizumab (compared with pembrolizumab alone…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS, defined as the time from randomization to the first documented disease
progression (based on Independent Review Committee (IRC) in accordance with
RECIST v1.1) or death from any cause. Patients who have not progressed or died
at the time of analysis will be censored at the date of assessment from their
last disease assessment.
Secondary outcome
• Overall Response Rate (ORR) defined as the percentage of patients achieving a
confirmed partial response (PR) or confirmed complete response
(CR). ORR will be determined by the IRC in accordance with RECIST v1.1.
• OS, defined as the time from randomization until death from any cause.
Patients not known to have died will be censored at the date they were last
known to be alive
• Duration of Response (DoR) based on IRC
• Time to Response (TTR) based on IRC
• Time to Complete Response (TTCR) based on IRC
• Disease Control Rate (DCR) based on IRC
• PFS and ORR, which will be assessed by the investigator according to RECIST
v1.1
Background summary
Cancer cells are naturally attacked by cells of the immune system, including
cytotoxic T- cells. Cancer cells can induce a state of tolerance whereby they
can escape this immune system response. This effect is brought about by many
different mechanisms; some of the most important are through overexpression of
the programmed death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1)
molecules and the metabolic enzyme indoleamine 2,3-dioxygenase (IDO). The PD-1
receptor is expressed on various cells, including T- cells. The blocking of
PD-1 on Tcells
by PD-1 blocking antibodies protects the T cells from the inactivation signal
from PD-L1 expressed by cancer cells or immune regulatory cells. In
treatment-naive patients with advanced melanoma, pembrolizumab (a PD-1 blocking
antibody) has previously been shown to provide a clinical response rate of 45%.
Spontaneous T*cell reactivity against PD-L1 and IDO has been identified in the
tumor microenvironment and in the peripheral blood of various cancer patients
and healthy donors. The IDO reactive CD8+ T-cells were cytotoxic and could kill
both cancer cells and immune regulatory dendritic cells in vitro. The PD-L1
reactive CD8+ T-cells were also cytotoxic and able to kill cancer cells and
myeloid derived suppressor cells (MDSCs). Therefore, boosting specific T-cells
that recognize immune regulatory proteins, such as IDO and PD-L1, may directly
modulate immune regulation. Due to the distinctive mechanisms of action, the
combination of treatment with a monoclonal antibody (mAb) targeting PD-1 and
IDO + PD-L1 peptides is hypothesized to have synergistic effects. There is
nothing to suggest that combining pembrolizumab with the experimental IDO and
PD-L1 peptides should be more toxic than treatment with pembrolizumab alone.
The PD-L1 peptide (PD-L19-27; IO103) and IDO peptide (IDO194*214; IO102) both
contain CD8+ T-cell epitopes as well as CD4+ T-cell epitopes. The PD*L1 and IDO
peptides boosts the natural immunity mediated by PD-L1 and IDO specific
T-cells. These can attack and kill regulatory immune cells and cancer cells, as
well as support additional anticancer immunity by the release of helper
cytokines.
In vivo proof-of-concept (PoC) studies in syngeneic mouse tumor models reveal
that IDO-targeting immunotherapeutic induces expansion of IDO-specific T-cells
in mice, leading to demonstrable antitumor therapeutic responses accompanied by
reduction of IDO+ immune suppressive cells in the tumor. In addition, efficacy
of IDO in a syngeneic mouse colon carcinoma model, CT26, is further improved by
coadministration of anti-PD-1 antibody. Currently, one ongoing trial
investigates IO102-IO103 in combination with nivolumab (PD-1 blocking antibody)
standard of care in patients with melanoma. The clinical trial is a Phase 1/2
trial and includes 30 patients with metastatic melanoma in a first line setting
(NCT03047928, MM1636). This ongoing, open-label, single-center trial started in
October 2017 and is investigating safety and efficacy of combination therapy
with nivolumab and the IDO/PD-L1 (IO102-IO103) dual-antigen immunotherapeutic.
Data from this trial has been reported and shows encouraging efficacy and a
manageable safety profile.
A summary of efficacy outcomes (5 October 2020) with a median duration of
follow-up of 23 months showed a confirmed response (PR or CR) was observed in
24 of 30 (80%) patients, of whom 13 of 30 (43.3%) patients experienced a CR. An
updated summary of outcomes was presented during AACR 2022 with a cutoff of 1
December 2021, the median progression free survival (mPFS) was 25.3 months and
median overall survival (mOS) was not reached. The three-year survival
probability is 73%.
Study objective
This study has been transitioned to CTIS with ID 2024-511996-13-00 check the CTIS register for the current data.
The primary objective is to investigate the efficacy of IO102-IO103 in
combination with pembrolizumab (compared with pembrolizumab alone) in terms of
progression-free survival (PFS). The secondary objectives are to further
explore the efficacy of IO102-IO103 in combination with pembrolizumab compared
with pembrolizumab alone in terms of ORR, OS, and CRR to investigate the safety
and tolerability of the treatment.
Study design
This clinical trial includes an initial safety evaluation of IO102-IO103 +
pembrolizumab and will be conducted approximately after the first 20 patients
have been randomized and received >=1 cycle to allow >=10 patients receiving
IO102-IO103+pembrolizumab to be evaluated.
Patients will be stratified based on the following factors:
• Disease stage: Stage III (unresectable) and IV M1a-b vs stage IV M1c-d
• Proto-oncogene B-Raf (BRAFV600) mutation status: mutated vs wild type
All patients will receive pembrolizumab 200 mg intravenous (IV) every three
weeks (Q3W) for a maximum of 35 cycles (up to 2 years treatment).
Patients randomized to IO102-IO103 will also be given IO102-IO103 subcutaneous
(SC) Q3W. The dose of each of IO102 and IO103 will be 85 *g. Each patient can
be treated for a maximum of 37 administrations in total (up to 2 years of
treatment).
An independent data monitoring committee (IDMC) will monitor the occurrence of
emerging adverse events (AEs). The IDMC charter will specify further details.
The trial will screen a total of approximately 500 patients and randomize 380
patients in approximately 100-125 sites in around 20 countries. Recruitment
will remain open until the required number of patients are randomized into the
trial. The total duration of the trial is approximately 70 months.
The overall trial begins when the first patient signs the informed consent
form. The overall trial ends after the final overall survival (OS) follow-up
analysis. Any patient remaining on treatment at this time will continue to
receive treatment for up to 35 (Q3W) cycles.
Following completion of trial treatment, patients are to be followed up after
trial treatment every 24 weeks for disease progression (if applicable) and
until the final survival update or death (whichever is earlier).
Intervention
Group 1: IO102-IO103: SC administration (IO102 85 µg and IO103 85 µg Q3W in
combination with pembrolizumab (IV administration 200 mg Q3W).
Group 2: Pembrolizumab: IV administration (200 mg Q3W).
Study burden and risks
A subject will undergo extra examinations and tests which make the visits last
longer than the subject is used to. Additionally, participation in this study
may affect the subject's eligibility for enrolling in a subsequent clinical
trial.
Ole Maaløesvej 3
Copenhagen DK-2200
DK
Ole Maaløesvej 3
Copenhagen DK-2200
DK
Listed location countries
Age
Inclusion criteria
- Histologically or cytologically confirmed stage III (unresectable) or stage
IV melanoma, as per American Joint Committee on Cancer 8th edition guidelines
not amenable to local therapy
- Patients are treatment naive, that is, no previous systemic anticancer
therapy for unresectable or metastatic melanoma. For clarification, the
following patients are eligible:
- Patients with proto-oncogene B-Raf (BRAFV600) mutation-positive melanoma are
eligible if treatment naive and without rapidly progressive disease as per
investigator assessment. Documented BRAFV600 mutation status must be available
from all patients prior to trial entry.
- Patients who have received previous adjuvant and/or neoadjuvant therapy with
targeted therapy or immune therapy are eligible if administered the last dose
at least 6 months before inclusion in this trial (randomization), and if
relapse did not occur during active treatment or within 6 months of treatment
discontinuation.
- ECOG performance status score 0 or 1 assessed within 10 days before
randomization
- At least 1 measurable lesion (not a cutaneous lesion) according to response
evaluation criteria for solid tumors (RECIST v1.1) and confirmed by IRC.
- Provision of archival (obtained within 3 months), or newly acquired biopsy
tissue not previously irradiated, and blood at screening for biomarker
assessments. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are
preferred to slides. Newly obtained biopsies are preferred to archived tissue.
- Patients are able and willing to provide written informed consent for the
trial in accordance with ICH-GCP and local legislation before admission to the
trial.
- Other protocol defined inclusion criteria may apply.
Exclusion criteria
- Uveal/ocular, acral or mucosal melanoma
- Patients with known or suspected central nervous system (CNS) metastases or
with the CNS as the only site of active disease are excluded with the following
exception:
* Patients with controlled (stable) brain metastases will be allowed to
enroll (subject to baseline confirmation). Controlled (stable) brain metastases
are defined as those with no radiographic progression for at least 4 weeks
after radiation and/or surgical treatment at the time of signed informed
consent. Patients must have been off steroids for at least 2 weeks before
signed informed consent and have no new or progressive neurological signs and
symptoms.
- Patient has received previous radiotherapy within 2 weeks of start of trial
treatment (visit 2). Patients must have recovered from all radiation-related
toxicities, not require corticosteroids, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (<=2 weeks
of radiotherapy) to non-CNS disease.
- Patients with BRAFV600-positive disease who are experiencing rapidly
progressing disease and/or have received standard first-line therapy with BRAF
and/or MEK inhibitor for unresectable or metastatic disease
- Received a live or live-attenuated vaccine within 30 days before the first
dose of trial treatment. Patients are also prohibited from receiving live or
attenuated vaccine(s) throughout the duration of protocol therapy and/or within
90 days of the last dose of protocol therapy. Administration of killed
vaccines, mRNA based (e.g., covid-19) and vector-based vaccines are allowed.
- Other protocol defined exclusion criteria may apply.
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 |
|---|---|
| EU-CTR | CTIS2024-511996-13-00 |
| EudraCT | EUCTR2021-004594-32-NL |
| ClinicalTrials.gov | NCT05155254 |
| CCMO | NL79874.041.22 |