To assess the safety and biodistribution of 89Zr-MEDI4736 and its uptake in tumor and target irAE tissues.
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* To assess the safety of 89Zr-MEDI4736.
* To assess uptake of 89Zr-MEDI4736 in tumor lesions.
Secondary outcome
* Assess uptake of 89Zr-MEDI4736 in normal tissues to evaluate the
biodistribution and dosimetry.
* Characterize tumor uptake heterogeneity between patients and within and
between tumor lesions of the same patient
* Correlate 89Zr-MEDI4736 tumor uptake with tumor and TIL PD-1 and PD-L1
expression as well as other blood and tissue parameters.
* Correlate 89Zr-MEDI4736 organ uptake with irAEs. The focus will be on the
lung, liver, thyroid, pancreas, kidneys and pituitary.
Background summary
Immune responses directed against tumors are one of the body*s natural defenses
against the growth and proliferation of cancer cells. However, over time and
under pressure from immune attack, cancers develop strategies to evade
immune-mediated killing allowing them to develop unchecked. One such mechanism
involves upregulation of surface proteins that deliver inhibitory signals to
cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein,
and is upregulated in a broad range of cancers with a high frequency, with up
to 88% expression in some tumor types. In a number of these cancers, including
lung, renal , pancreatic, ovarian cancer, and hematologic malignancies, tumor
cell expression of PD-L1 is associated with reduced survival and an unfavorable
prognosis.
PD-L1 acts at multiple sites in the body to help regulate normal immune
responses and is utilized by tumors to help evade detection and elimination by
the host immune system tumor response. In the lymph nodes, PD-L1 on
antigen-presenting cells binds to PD-1 or CD80 on activated T cells and
delivers an inhibitory signal to the T cell . This results in reduced T-cell
activation and fewer activated T cells in circulation. In the tumor
microenvironment, PD-L1 expressed on tumor cells binds to PD-1 and CD80 on
activated T cells reaching the tumor. This delivers an inhibitory signal to
those T cells, preventing them from killing target cancer cells and protecting
the tumor from immune elimination.
MEDI4736 is being developed as a potential anticancer therapy for patients with
advanced solid tumors. MEDI4736 binds with high affinity and specificity to
human PD-L1 and blocks its interaction with PD-1 and CD80. In vitro studies
demonstrate that MEDI4736 antagonizes the inhibitory effect of PD-L1 on primary
human T cells, resulting in their restored proliferation and release of
interferon gamma (IFN-*).
To identify patients that will benefit the most from treatment with mAbs like
MEDI4736, better knowledge of the in vivo behavior of the drug is warranted.
For this, positron emission tomography (PET) imaging with radiolabeled mAbs
(immuno-PET) is an attractive option. In this study, MEDI4736 will be
radiolabeled with 89Zirconium (89Zr-MEDI4736). 89Zr-MEDI4736 quantifies the
PD-L1 receptor on tumor cells, the most important (ex-vivo) tissue biomarker
for patient selection in current trials with anti-PD-(L)1 mAbs. With
89Zr-MEDI4736 PET it will be possible to perform in vivo PD-L1
immunohistochemistry and provide unique insight in the performance of tumor
tissue PD-L1 IHC.
Study objective
To assess the safety and biodistribution of 89Zr-MEDI4736 and its uptake in
tumor and target irAE tissues.
Study design
Single arm open label exploratory pilot (imaging) study. To visualize the PD-L1
pathway, positron emission tomography will be combined with the radiolabeled
anti-PDL1 monoclonal antibody MEDI4736. Imaging with 89Zr-MEDI4736 allows for
non-invasive quantification of its direct target, the PD-L1 receptor on the
tumor cells, the most important biomarker for patient selection in current
trials with anti-PD-(L)1 mAbs. Because the technique is non-invasive and whole
body, it allows for serial measurements of tumor uptake as well as looking at
heterogeneity within and between tumor lesions. After 89Zr-MEDI4736 injection
(day 0), sequential PET imaging will be performed at 1 hour, 72 hours and 120
hours post injection. On day 12, 89Zr-MEDI4736 will be injected within two
hours after a therapeutic non-radiolabeled dose of MEDI4736, followed by
sequential PET imaging to minimize the possibility of negative imaging
findings. At a tracer dose the labeled antibody may not sufficiently reach the
target due to sink effects in e.g. liver, spleen, blood or other
compartments/organs. After a therapeutic non-radiolabeled dose, 89Zr-MEDI4736
may not accumulate in the tumor due to saturation of the PD-L1 target by the
therapeutic dose. After enrollment of the first three patients the data will be
analyzed. When tumor targeting is not seen with both imaging strategies, the
dose of non-radiolabeled MEDI4736 might be adjusted.
To correlate the imaging results to tumor and peripheral immune parameters like
PD-1, PD-L and T cell subsets, tumor and blood samples will be obtained at
baseline. Two additional biopsies are allowed in case the PET scans show
heterogeneous uptake between tumor lesions of the same patient. In this way,
imaging with 89Zr-MEDI4736 PET will aid further validation of PD-L1 IHC.
89Zr-MED4736 might also predict for immune related adverse events (irAE). Whole
body imaging allows to quantify MEDI4736 binding in target irAE tissues and the
level of tracer uptake might predict for irAEs. Imaging results will be
correlated to irAE findings during MEDI4736 treatment. From day 12 on, patients
will be treated with 750 mg MEDI4736 IV Q2W until disease progression or
unacceptable toxicity and to a maximum of 12 months.
Intervention
Not applicable
Study burden and risks
No toxicity is expected from PET scans with tracer microdoses. The amount of
89Z-MEDI4736 (2 mg) is far below the MEDI4736 dose that is used in clinical
studies and a pharmacological effect is therefore not anticipated. The total
amount of radiation exposure is substantial, but immediate effects are not
anticipated and because of the limited life expectancy of patients with stage
IV NSCLC the long term risk of developing a secondary malignancy due to
radiation exposure is only theoretical. Patients do not derive benefit from the
PET scan results. Since there is a lack of a well performing predictive
biomarker of response, the results of this imaging biomarker study can be of
high interest for NSCLC patients that are eligible for anti-PD-(L)1 treatment
in the future.
Up to two on study biopsies are allowed in this study (after the first and
before the second 89Zr-MEDI4736 PET scan) in case the first 89Zr-MEDI4736 PET
scan shows heterogeneous uptake between tumor lesions in individual patients
(defined in section 3.1.2). Although this is demanding for patients, tumor
biopsies in lung cancer patients are considered safe with a low and manageable
complication rate. These biopsies will be used to explain heterogeneous tracer
uptake and relate the imaging results to that of the tissue biomarkers PD-1 IHC
(locally) PD-L1 IHC (Ventana assay using SP263).
The overall response rate for second line treatment with single agent
chemotherapy is ~10%. In a phase I trial of MEDI4736, 14% of 149 patients with
advanced NSCLC had a best overall response of complete response (CR)/partial
response [Rizvi N, ASCO 2015, Abstract ID 8032]. MEDI4736 is therefore a very
promising drug for the treatment of NSCLC in the second line setting and
beyond. It is therefore not unlikely that patients derive benefit from this
study. As can be found in the Investigator*s Brochure, the toxicity is
manageable and the safety profile acceptable.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
For inclusion in the study subjects must fulfill all of the following criteria:
* Have a histologically or cytologically confirmed diagnosis of stage IV, EGFR wt and EML4-ALK fusion negative NSCLC and have received at least one line of platinum based doublet chemotherapy.
* Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
* Age > 18 years at time of study entry
* Have a World Health Organisation (WHO) performance status of 0 or 1
* Life expectancy of more than 3 months.
* Have measurable disease based on RECIST 1.1.
* Must provide tissue from a histological biopsy of a tumor lesion that is not radiated prior to biopsy and obtained after the last line of systemic therapy to determine the PD-L1 status.
* Willing to undergo up to two additional biopsies when the first 89Zr-MEDI4736 PET scan shows heterogeneous uptake.
* Adequate normal organ and marrow function.
* Females of childbearing potential must use reliable methods of contraception from the time of screening until 3 months after discontinuing study treatment.
* Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study.
* Participation in another clinical study with an investigational product during the last 4 weeks.
* Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736.
* History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease *3 years before the first dose of study drug. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ.
* Receipt of the last dose of anti-cancer therapy * 14 days prior to the first dose of study drug.
* Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
* Any unresolved toxicity (CTCAE grade <2) from previous anti-cancer therapy.
* Any prior Grade *3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
* Active or prior documented autoimmune disease within the past 2 years requiring systemic steroid treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids. NOTE: Subjects with vitiligo, Grave*s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
* Active or prior documented inflammatory bowel disease (e.g., Crohn*s disease, ulcerative colitis)
* History of primary immunodeficiency
* History of allogeneic organ transplant
* History of hypersensitivity to MEDI4736 or any excipient
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
* Known history of previous clinical diagnosis of tuberculosis
* History of leptomeningeal carcinomatosis
* Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736
* Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
* Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
* Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids exceeding a daily dose equivalent of 10 mg prednisolone. Patients with asymptomatic brain metastases are allowed if these do not exceed a maximal diameters of 2 cm.
* Subjects with uncontrolled seizures.
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 | EUCTR2015-005765-23-NL |
| CCMO | NL59976.029.16 |