To determine FRAME-001-specific immune responses in peripheral blood after administration of FRAME-001 to patients with advanced NSCLC.Secondary objectives- To assess safety and tolerability of FRAME-001.- To evaluate clinical anti-tumor response to…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective:
- To determine FRAME-001-specific immune responses in peripheral blood after
administration of FRAME-001 to patients with advanced NSCLC.
Primary endpoint:
- Antigen-specific immune responses in peripheral blood to one or more Frame
peptides following application of a personalized FRAME-001 vaccine, based on a
positive outcome in one or more of the following assays:
4-Day interferon gamma (IFNg) enzyme-linked immunospot (ELISpot) assay
IFNg, tumor necrosis factor alpha (TNFa), and/or interleukin-2 (IL-2) producing
CD4+ and/or CD8+ T cells determined in intracellular cytokine staining assay
Specific cytokine production as measured by Th1/Th2 cytokine bead array in
culture supernatants.
Secondary outcome
Secondary endpoints
- Incidence, type, grade, and number of adverse events (AEs) according to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) version 5.0.
- Tumor response and tumor response duration according to Response Evaluation
Criteria in Solid Tumors (RECIST) v.1.1 criteria.
- Progression-free survival (PFS) and overall survival (OS).
Exploratory endpoints
- Phenotypic composition of and functional changes in immune cells in
peripheral blood and changes in plasma cytokine levels after vaccination with
FRAME-001 determined by immunomonitoring assays, including but not limited to
multiparametric flow cytometry, enzyme-linked immunoadsorbent assay (ELISA),
functional T cell assays (T cell proliferation, cytokine production), T cell
receptor repertoire, and other relevant immunological assays.
- Relative change in immune cell infiltration and expression of PD-1 on tumor
infiltrating lymphocytes and PD-L1 on tumor and immune cells in tumor biopsy
(if available) after vaccination with FRAME-001.
- Analysis of ctDNA in plasma.
- Correlation of immune responses to PD-L1 expression of the tumor, and to
Framome status.
Background summary
Despite encouraging results of programmed cell death protein -1 (PD-1) immune
checkpoint inhibitor treatment combined with chemotherapy in advanced non-small
cell lung cancer (NSCLC), only the minority of approximately 20% of patients
derive durable clinical benefit from such treatment. Patients with stable
disease (SD) after four cycles of treatment with PD-1 inhibitor pembrolizumab
monotherapy or in combination with chemotherapy (standard of care in advanced
NSCLC in the Netherlands) have a low probability of still acquiring a complete
response (CR) or durable disease control to such treatment and no other
curative standard treatment options are available, emphasizing the need for
novel therapeutic approaches. Tumor-specific neopeptides resulting from
frameshift mutations in tumor cells, so-called Frames, present potentially
potent targets for the immune system and can be utilized in therapeutic
anti-cancer vaccination with the intention to synergize in their effect with
immune chckpoint inhibitors. Frames are prevalent in NSCLC patients, with 95%
of lung tumors harboring one or more Frames. The entire collection of Frames
expressed by a tumor is referred to as the*Framome. Vaccination against
strongly antigenic neopeptides present in a patient*s tumor furnishes a
perspective of enhancing the therapeutic effect of the immune checkpoint
inhibition in NSCLC with expected limited additional toxicities. The current
clinical trial is designed to determine immune response, safety, and clinical
response of personalized vaccine FRAME-001 based on a patient*s Framome and
selection of Frame peptides in advanced NSCLC cancer patients after standard
first line treatment consisting of immune checkpoint inhibitor pembrolizumab as
monotherapy or combined with chemotherapy (carboplatin/cisplatin and
pemetrexed/paclitaxel), and who attained SD after four cycles of such therapy.
The personalized FRAME-001 vaccine will be administered during maintenance
phase of treatment with pembrolizumab monotherapy.
Study objective
To determine FRAME-001-specific immune responses in peripheral blood after
administration of FRAME-001 to patients with advanced NSCLC.
Secondary objectives
- To assess safety and tolerability of FRAME-001.
- To evaluate clinical anti-tumor response to FRAME-001.
- To assess survival after treatment with FRAME-001.
Exploratory objectives
- To determine changes in the peripheral blood immune profile following
FRAME-001 vaccination.
- To assess molecular responses based on circulating tumor DNA (ctDNA) in
plasma.
- To assess immune responses in the tumor tissue before and after
administration of FRAME-001.
- Correlate FRAME-001-specific immune response to PD-L1 expression of the tumor
and to Framome status.
Study design
Prospective, single arm, multi center, open-label, phase II clinical trial
Intervention
Patients will receive personalized peptide vaccine FRAME-001 based on
frame-shift mutations (Frames) detected by Whole Genome Sequencing
(WGS)/Ribonucleic Acid sequencing (RNAseq) in a tumor biopsy. FRAME-001 vaccine
will contain up to 24 peptides divided over four vials (each up to six
peptides) admixed with immune adjuvant Montanide ISA 51 VG and will be
administered in four sequential cycles at 3-week interval (Q3W), along standard
maintenance monotherapy of pembrolizumab (administration Q3W or Q6W). Each
cycle will be consisting of up to four subcutaneous injections at up to four
different sites in the upper and lower limbs.
Study burden and risks
Please see the Investigator's Brochure (IB) for a detailed background and data
on FRAME-001
Science Park 106
Amsterdam 1098XG
NL
Science Park 106
Amsterdam 1098XG
NL
Listed location countries
Age
Inclusion criteria
- Age *18 years.
- Eastern Cooperative Oncology Group (ECOG) performance status * 1
- -Pathologically and radiologically confirmed advanced squamous or
non-squamous NSCLC with SD after four cycles of treatment with pembrolizumab as
monotherapy or in combination with chemotherapy (carboplatin/cisplatin and
pemetrexed/paclitaxel) and suitable for maintenance treatment with
pembrolizumab monotherapy.
- Patient Framome identification with demonstrated frameshift mutations
(Frames) completed as part of molecular pre-screening:
o Presence of at least 3 expressed frameshift mutations;
o A combined length of *100 amino acids for the neopeptides resulting from the
frameshifts, with preferably more than 100 amino acids.
o No mutations/genetic aberrations in genes relevant for MHC presentation
(e.g., beta-2-microglobulin, human leukocyte antigen [HLA] genes).
- An expected survival of at least 3 months.
- Presence of tumor lesion(s) suitable for biopsy and radiological assessment
as per RECIST v1.1 criteria.
- Adequate renal function as defined by creatinine clearance > 40 mL/min
based on the Cockroft-Gault glomerular filtration rate (GFR).
- Adequate hepatic function as evidenced by:
o Serum total bilirubin * 2.5 × upper limit of normal (ULN) unless considered
due to hepatic metastases.
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
alkaline phosphatase (ALP) * 3.0 × ULN, unless considered due to hepatic
metastases.
- Ability to return to the hospital for adequate follow-up as required by this
protocol.
- For all women of childbearing potential (defined as < 2 years after last
menstruation or not surgically sterile) must have a negative highly sensitive
pregnancy test at screening (serum/urine) and agree to use highly effective
method of contraconception according to European Union (EU) Clinical Trial
Facilitation Group guidance from time of signing informed consent form until at
least 120 days after the last administration of FRAME-001. The partners of
participants of childbearing potential must also apply contraceptive methods
and are recommended not to donate sperm.
- Written informed consent according to International Conference on
Harmonisation (ICH)-Good Clinical Practice (GCP).
Exclusion criteria
- Any active infection that according to investigator might interfere with
FRAME-001 vaccination.
- Patients planned or foreseen to receive systemic immunosuppressive treatment
including corticosteroids during the trial are not eligible.
- Use of systemic corticosteroids (or other immunosuppressive agents; >10mg
daily prednisone equivalent). Inhaled, intranasal or topical and physiological
replacement doses of up to 10 mg daily prednisone equivalent are permitted.
- Live vaccine within 30 days prior to first dose of FRAME-001.
- Concomitant participation in another clinical intervention trial (except
participation in a
biobank study).
- Pregnant or lactating women.
- Known allergy to any of the ingredients of the vaccine (i.e., synthetic long
peptides, Montanide ISA 51 VG).
- Any medical or psychological condition deemed by the Investigator to be
likely to interfere with a patient*s ability to give informed consent or
participate in the study.
- Any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule.
- Patients with a currently active second malignancy. However, patients with
the following history/concurrent conditions are allowed:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer.
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 | EUCTR2021-003166-12-NL |
| ClinicalTrials.gov | NCT04998474 |
| CCMO | NL78379.000.21 |