This study has been transitioned to CTIS with ID 2024-512616-21-00 check the CTIS register for the current data. The main objective of the trial is to determine the pathological response rate in cohort 1 and the radiological response rates in cohort…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pathologic response of the primary tumor in patients with HNSCC and objective
response rate according to RECIST 1.1 and iRECIST in patients with advanced or
metastatic MSI-H cancer, metastatic melanoma, and patients with a locally
advanced or metastatic solid tumor whom, in the opinion of the investigator,
based on available clinical data, may benefit from treatment with anti-PD-L1
immunotherapy.
Secondary outcome
The secondary endpoints are toxicity scored according to the common criteria
for adverse events version 5.0, disease free survival in patients with HNSCC,
overall response rate, progression free survival and duration of response in
the patients in cohort 2, 3 and 4 as well as The correlation between the
expression of the proteins TIGIT, PD-1, PD-L1 and CD8 on tumor tissue and
pathologic and radiographic response rate.
Background summary
Tumor immunotherapy has demonstrated that therapies focused on enhancing T cell
responses against cancer can result in a significant survival benefit in
subjects with advanced stages of cancer. The most frequently used immunotherapy
drugs bind to the Programmed death-ligand 1 (PD-L1) or programmed death protein
1 (PD-1). This binding interrupts the PD-L1/PD-1 pathway which inhibits an
anti-tumor response of the immune system. Not all patients respond to anti-PD-1
or anti-PD-L1 treatment and therefore, combinations of immunotherapy drugs have
been investigated and proven more effective than single-agent immunotherapy.
These combinations, however, also increase the chance of immune toxicity.
Possible strategies to overcome this problem are to develop less toxic
combinations of immunotherapy drugs.
The T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) protein
is also a target for immunotherapy. TIGIT is overexpressed in several
malignancies including, melanoma, head and neck squamous cell carcinoma
(HNSCC), and microsatellite instability high (MSI-H) colorectal cancer. The
combination of the anti-TIGIT drug tiragolumab with the anti-PD-L1 drug
atezolizumab increased the overall response rate by 15.1% compared to
atezolizumab alone in a phase 2 study with 135 non-small cell lung cancer
patients (NSCLC), without increasing toxicity.
In this trial, we will assess anti-tumor activity, safety, and tolerability of
atezolizumab in combination with tiragolumab in subjects with cancer. We will
also investigate proteins in the tumor to determine if we can predict which
patients will respond to the atezolizumab and tiragolumab treatment. Patients
will be included in one of four cohorts, namely: cohort 1, patients with
localized HNSCC who will be treated with atezolizumab and tiragolumab followed
by tumor resection, cohort 2, patients with metastatic MSI-H tumors, cohort 3,
patients with irresectable or metastatic melanoma who progressed after PD-1
treatment, or cohort 4, with patients with a locally advanced or metastatic
solid tumor for whom, based on available clinical data, treatment with
anti-PD-L1 immunotherapy may be beneficial. Acquired data could lead to
improved, more patient-tailored immune checkpoint inhibition.
Study objective
This study has been transitioned to CTIS with ID 2024-512616-21-00 check the CTIS register for the current data.
The main objective of the trial is to determine the pathological response rate
in cohort 1 and the radiological response rates in cohort 2, 3 and 4. The
secondary objectives of the trial are the safety of atezolizumab and
tiragolumab, the response rates measured by overall response rate, disease free
survival rate, duration of response and the last secondary objective is to
determine the correlation between the protein expression of different proteins
involved in the immune response of cancer to immunotherapy and the different
response rates as mentioned before.
Study design
Open label phase 2 basket trial with atezolizumab and tiragolumab in patients
with localized HNSCC who will undergo surgery, and advanced or metastatic MSI-H
cancer, PD-1 resistant metastatic melanoma, and patients with a locally
advanced or metastatic solid tumor who, in the opinion of the investigator,
based on available clinical data, may benefit from treatment with anti-PD-L1
and anti-TIGIT immunotherapy.
Intervention
Subjects will receive atezolizumab and tiragolumab every 3-weeks until 1)
resection as scheduled for HNSCC after 2 courses, 2) resectable disease for the
MSI-H tumors, 3) progressive disease or side effects requiring treatment
termination or 4) a maximum of 2 years. At baseline archival tissue or a tumor
biopsy will be obtained and tissue will be collected once during the trial and
when lesions are surgically resected. Blood samples will be collected during
the trial to measure circulating tumor DNA. During the trial regular CT or MRI
scans will be made to monitor the response to the treatment.
Study burden and risks
Encouraging clinical data emerging in the field of tumor immunotherapy have
demonstrated that therapies focused on enhancing T cell responses against
cancer can result in a significant survival benefit in patients with cancer.
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in
patients with advanced malignancies, who have failed standard of care
therapies.
Patient are required to provide tumor material during screening and on
treatment. For cohort 1 this will be the archival diagnostic biopsy and the
surgical specimen. For cohort 2, 3 and 4, the pre-treatment biopsy can be
replaced by archival tissue provided that this tissue was obtained at the time
of metastatic or irresectable disease, which holds no risk for patients. Based
on a literature review, the risk of tumor biopsies is considered low with a
small risk on significant/major complications (0 to 1.6%) or death (0 to 0.48%).
For patients with HNSCC there is a risk of delay of surgery due to toxicity of
the atezolizumab and tiragolumab treatment as well as progressive disease and
subsequent loss of resectability. These risks are however deemed limited
because of the short duration of the neo-adjuvant treatment in the study. In
order to account for the possibility of pseudoprogression/tumor immune
infiltration (i.e., radiographic increase in tumor volume due to the influx of
immune cells) and the potential for delayed anti-tumor activity, this trial.
Subjects will be allowed to receive atezolizumab and tiragolumab beyond
apparent radiographic progression in cohort 2, 3 and 4. Because it is not yet
possible to reliably differentiate pseudoprogression/tumor immune infiltration
from true tumor progression, the risk exists that some subjects not responding
to treatment yet continuing to receive atezolizumab and tiragolumab may
experience a decline in performance status related to progression and may not
be fit to receive subsequent therapies for which they would otherwise have been
eligible. Investigators will make every effort to fully inform subjects of this
risk. In contrast to the cytotoxic therapies approved for treatment,
atezolizumab and tiragolumab have been generally well tolerated and have not
been associated with bone marrow suppression or other systemic toxicities
(i.e., neuropathy, nephrotoxicity, or febrile neutropenia) that may limit the
ability to administer subsequent treatments.
In summary, treatment with atezolizumab and tiragolumab offers the potential
for clinical benefit in subjects. Because most atezolizumab and tiragolumab
-related toxicities observed to date have been mild and transient in nature and
do not overlap with the adverse effects of chemotherapy, subjects who do not
respond to study treatment are considered likely to be able to subsequently
receive standard therapies for which they would otherwise have been
eligible. Subjects will be fully informed of the risk of continuing study
treatment in spite of apparent radiographic progression, and investigators
should make a careful assessment of the potential benefit of doing so,
considering radiographic data, biopsy results, and the clinical status of the
subject.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
• Tumor lesion(s) of which a histological biopsy can be safely obtained
according to standard clinical care procedures.
• Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions
should be discarded as target lesions.
• Participate in the GE-269-001 CD8 investigational imaging trial provided that
there are slots is that trial.
• Signed informed consent.
• Age >=18 at the time of signing informed consent.
• Life expectancy >=12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 5)
• Adequate organ and bone marrow function as defined below:
o Hemoglobin >=9.0 g/dL
o Platelet count >=100 x 109 /L
o Serum creatinine <=1.5 x upper limit of normal (ULN) or estimated glomerular
filtration rate > 30 mL/min/1.73 m2 . A 24-hour urine creatinine collection
may substitute for the calculated creatinine clearance to meet eligibility
criteria.
o Adequate hepatic function:
* Total bilirubin <=1.5 x ULN (<=3 x ULN if liver tumor involvement); Patients
with Gilbert*s syndrome do not need to meet total bilirubin requirements,
provided their total bilirubin is unchanged from their baseline. Gilbert*s
syndrome must be documented appropriately as past medical history.
* Aspartate aminotransferase (AST) <=2.5 x ULN (<=5 x ULN if liver tumor
involvement)
* Alanine aminotransferase (ALT) <=2.5 x ULN (<=5 x ULN if liver tumor
involvement)
* Alkaline phosphatase (ALP) <=2.5 x ULN (<=5 x ULN if liver or bone tumor
involvement)
• Ability to comply with the protocol.
• For female patients of childbearing potential and male patients with partners
of childbearing potential, agreement (by the patient and/or partner) to use a
highly effective form(s) of contraception (i.e., one that results in a low
failure rate (< 1% per year) when used consistently and correctly).
For the head and neck squamous cell carcinoma cohort specific eligibility
criteria apply
• clinical T2-4a, or node positive resectable HPV-unrelated HNSCC (oral cavity,
larynx, hypopharynx, p16-negative oropharynx or p16 negative unknown primary)
• no evidence of distant metastases
• no previous radiotherapy to the head and neck region
Exclusion criteria
• Signs or symptoms of infection within 2 weeks prior to atezolizumab and
tiragolumab administration.
• Prior immune checkpoint inhibitor treatment, including but not limited to
anti-PD1 and anti-PD-L1 antibodies (only for cohort 1, 2 and 4).
• History of severe allergic, anaphylactic, or other hypersensitivity reactions
to chimeric or humanized antibodies or fusion proteins.
• Any other diseases, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or
condition that contraindicates the use atezolizumab and tiragolumab, or that
may affect the interpretation of the results or render the patient at high risk
from complications.
• Pregnant or lactating women.
• Positive test for HIV, active hepatitis B (chronic or acute defined by
positive hepatitis B surface antigen (HBsAg) during screening) or hepatitis C.
Patients with a medical history of hepatitis B infection (defined as a positive
hepatitis B core antibody (HBcAb) and absence of an HBsAg) are eligible for
this study. Patients who test positive for hepatitis C antibodies are only
eligible with a negative hepatitis C RNA PCR.
• Acute or chronic active EBV infection at screening EBV status should be
assessed by EBV serology (e.g., anti-VCA IgM and IgG, anti-EA IgG, anti-EBNA
IgG) and EBV PCR (plasma or serum). If EBV serology results indicate prior EBV
infection, patients must have a negative EBV PCR (plasma or serum) to be
eligible for the study.
• Active tuberculosis.
• Treatment with systemic immunostimulatory agents (including but not limited
to interferons (IFNs) or, IL-2). The agents may not have been used within 6
weeks or five half-lives of the drug, whichever is shorter, prior to the first
full dose of atezolizumab and tiragolumab.
• Treatment with systemic immunosuppressive medications (including but not
limited to prednisone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor (TNF) agents) within 2 weeks prior
to cycle 1, day 1, with the exception of inhaled corticosteroids for chronic
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for
subjects with orthostatic hypotension, low-dose supplemental corticosteroids
for adrenocortical insufficiency and topical steroids are allowed.
• medications (e.g., a one-time dose of dexamethasone for nausea) may be
allowed in the study after discussion with and approval by the principal
investigator (PI).
• Brain metastases, leptomengeal metastases.
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 | CTIS2024-512616-21-00 |
| EudraCT | EUCTR2021-006894-48-NL |
| ClinicalTrials.gov | NCT05483400 |
| CCMO | NL82143.042.22 |