The primary objective of the exploratory study is to characterize the types and dynamics of changes in the tumor microenvironment that occur following programmed-death-1 (PD-1) receptor blockade with REGN2810 and to assess their relationship to the…
ID
Source
Brief title
(0456/0086)
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms benign
- Skin neoplasms malignant and unspecified
Synonym
Health condition
melanoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The correlation between changes in the tumor microenvironment and the change in
tumor volume following REGN2810 treatment versus baseline.
The changes in tumor microenvironment that will be correlated to the change in
tumor volume may include:
* Changes in number of immune cells in the tumor microenvironment:
o Changes in the number of tumor infiltrating lymphocytes (TILs) focusing on
CD8+ T cells, CD4+ T cells, Tregs and myeloid cells
o Changes in cell type representation in the immune cell infiltrate (normalized
against total number of TILs)
* Fold-change in tumor gene expression focusing on the top 10 genes
differentially affected in responders compared to non-responders (changes in
expression of additional genes of interest may be evaluated as part of the
exploratory analyses)
* Changes in positive and negative immune checkpoint modulator expression
focusing on LAG3, TIM3, and GITR (other molecules of interest may be evaluated
as part of the exploratory analyses):
o Changes in overall expression level (assessed by RNASeq) and in situ
expression (assessed by RNAScope)
* Changes in number of cells expressing molecule of interest.
Secondary outcome
* Correlation between baseline tumor characteristics and the change in tumor
volume following treatment in REGN2810.
o Tumor gene expression as assessed by tumor RNASeq
o Tumor mutational load as assessed by whole-exome DNA sequencing and
comparison between somatic and germline DNA
* Adverse Event (AEs) in patients treated with REGN2810.
* Concentrations of REGN2810 in serum and anti-REGN2810 antibody levels
* The overall response rate (ORR) and progression-free survival (PFS) in
patients treated with REGN2810.
Background summary
This is an exploratory study with a limited sample size and the analysis in
this study will be descriptive and hypothesis generating. The primary
hypotheses the study explores are:
* There are changes in the tumor microenvironment that occur following PD-1
blockade with REGN2810.
* There is a correlation in the tumor microenvironment that occur following
PD-1 blockade with REGN2810 and clinical response as defined by changes in
tumor volume.
A fixed sample size of 30 patients was initially selected based on clinical and
feasibility considerations. With 30 patients, the (In order to obtain a
better representation of patients with non-acral cutaneous subtype(s) of
melanoma in this study, the overall sample size will be increased up to 50
patients). The precision of correlation between changes in tumor
microenvironment and changes in tumor volume can be estimated using FISHER Z
transformation. The primary analysis set includes all patients who have passed
screening and deemed to be eligible for this study. Eligible patients are
defined as patients with a tumor assessment at screening and at least one
post-baseline tumor assessment. Additionally, patients must have biomarker data
that meet QC criteria at baseline and at least one post treatment assessment.
For continuous variables, descriptive statistics will include the following
information: the number of patients reflected in the calculation (n), mean,
median, standard deviation, minimum, and maximum. For categorical or ordinal
data, frequencies and percentages will be displayed for each category. In
general, the biomarker data will be transformed prior to relating fold change
from baseline to clinical endpoints.
Secondary endpoints will be analyzed using the similar methods described in
analysis of primary endpoint.
Baseline characteristic and adverse events will be summarized using descriptive
statistics.
Due to exploratory nature of the study, uncertainty in measurability and
variability of biomarker variables and no formal hypothesis testing, the
multiplicity control is not applicable to this study.
Study objective
The primary objective of the exploratory study is to characterize the types and
dynamics of changes in the tumor microenvironment that occur following
programmed-death-1 (PD-1) receptor blockade with REGN2810 and to assess their
relationship to the clinical response as defined by changes in tumor volume.
Specific techniques will include:
* Changes in immune cell infiltrates (as measured by RNASeq, RNAScope in situ
hybridization and/or immunohistochemistry (IHC), if needed and available) to
determine number, subset ratios, and geographic distribution of CD8+ T cells
and other immune cells (for example, CD4+ T cells, B cells, NK cells,
myeloid-derived suppressor cells, etc.).
* Changes in positive and negative immune checkpoint modulator expression (as
assessed by RNASeq, in situ gene expression by RNAScope in situ hybridization
and/or protein levels by IHC, if needed and available), of LAG3, TIM3, GITR,
and other molecules of interest.
The secondary objectives of the exploratory study are:
* To assess the correlative relationship between baseline tumor characteristics
and the changes in tumor volume following treatment with REGN2810.
* To assess the safety and tolerability of REGN2810.
* To measure drug concentrations during treatment.
* To assess immunogenicity of REGN2810.
* To assess the overall response rate (ORR) and progression-free survival (PFS)
of melanoma patients treated with REGN2810.
For the additional exploratory objectives refer to the protocol.
Study design
This is a single-arm, multicenter, biomarker-driven trial evaluating the
relationship between tumor and immune-related biomarkers and clinical response
in immunomodulatory treatment-naïve unresectable stage III/IV melanoma patients
receiving REGN2810 (anti-PD-1).
After a screening period of up to 28 days, patients will receive treatment with
REGN2810 every 2 weeks up to 24 doses (48 weeks).
Each patient will receive 3 mg/kg REGN2810 given as a 30-minute infusion. Tumor
assessments will be made every 8 weeks by imaging. Extensive safety evaluations
will occur every 8 weeks; routine safety evaluations will be conducted at each
REGN2810 dosing visit.
A patient will receive treatment until the 48-week treatment period is
complete, or until disease progression, unacceptable toxicity, withdrawal of
consent, or confirmed complete response (CR). Patients with confirmed CR after
a minimum of 24 weeks of treatment may elect to discontinue treatment.
Patients with a single tumor assessment of PD (without prior partial response
[PR]/CR) may continue treatment with the experimental regimen until the next
tumor assessment, at the discretion of the investigator, based on the clinical
state of the patient. Patients with confirmed and increasing PD per Response
Evaluation Criteria in Solid Tumors (RECIST) criteria (2 radiologic assessments
of PD at least 4 weeks apart), or patients who are rapidly progressing and/or
experiencing significant clinical deterioration or study drug toxicity, should
discontinue study treatment.
Patients who discontinue study treatment will be followed for survival
approximately every 3 months until death, lost to follow-up, or study
termination by the sponsor.
Intervention
Each patient will receive 3 mg/kg REGN2810 given as a 30-minute infusion.
Maximum of 24 doses.
Study burden and risks
The emerging safety profile of REGN2810 is consistent with that described in
the clinical literature for other antibodies directed against PD-1.
In the dose-escalation cohort of R2810-ONC-1423 study, REGN2810 was
well-tolarated; no DLTs were reported when administered to patients with
advanced solid tumors at doses of 1,3, or 10 mg/kg either as monotheprapy or in
combination with hypofractionated radiation and/or cyclophosphamide. In this
heavily pre-treated phase 1 population of patients with solid malignancies,
including tumor types known to respond poorly to PD-1/PD-L1 blockade, an
overall response rate of 18.3% indicates that REGN2810 is a clinically active
inhibitor of the PD-1 pathway. In study R1979-ONC-1504, the emerging data show
that REGN2810 is well-tolerated in patients with lymphoma.
The benefit-risk profile continues to be positive in both solid tumors and
lymphomas supporting further study of REGN2810.
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Old Saw Mill River Road 777
Tarrytown NY 10591
US
Listed location countries
Age
Inclusion criteria
1. Histologically confirmed diagnosis of stage III (unresectable) or stage IV
cutaneous (non-acral lentiginous) with at least 1 lesion that is measurable by
RECIST 1.1 criteria and accessible for biopsies. , 2. Eastern Cooperative
Oncology Group (ECOG) performance status (PS) of 0 or 1 (ECOG PS 1 definition:
Restricted in physically strenuous activity but ambulatory and able to carry
out work of a light or sedentary nature, eg, light house work, office work).,
3. *18 years old, 4. Hepatic function:, a. Total bilirubin *1.5 x upper limit
of normal, b. Transaminases *3 x ULN, c. Alkaline phosphatase (ALP) *2.5 x ULN,
5. Serum creatinine *1.5 x ULN or estimated glomerular filtration rate >50
mL/min/1.73m^2, 6. Bone marrow function:, a. Hemoglobin *9.0 g/dL, b. Absolute
neutrophil count (ANC) *1.5 x 10^9/L, c. Platelet count *75 x 10^9/L, 7.
Willing and able to comply with clinic visits and study-related procedures, 8.
Provide signed informed consent, 9. Able to understand and complete
study-related questionnaires, 10. Anticipated life expectancy >12 weeks
Exclusion criteria
1. Ongoing or recent (within 5 years) evidence of significant autoimmune
disease that required treatment with systemic immunosuppressive treatments,
which may suggest risk for irAEs., 2. Prior treatment with an agent that blocks
the PD-1/PD-L1 pathway., 3. Prior treatment with other immune modulating
anti-cancer agents., 4. Untreated or active brain metastases or spinal cord
compression. , 5. Immunosuppressive corticosteroid doses, 6. History of human
immunodeficiency virus (HIV)., 7. Uncontrolled chronic hepatitis B or C., 8.
History of pneumonitis within the last 5 years., 9. Grade 3 or 4 hypercalcemia
at time of enrollment., 10. Any systematic anticancer treatment,
investigational or standard of care, within 30 days of the initial
administration of REGN2810 or planned to occur during the study period (Patients
receiving bisphosphonates or denosumab are not excluded)., 11. History of
documented allergic reactions or acute hypersensitivity reaction attributed to
antibody treatments., 12. Known allergy to doxycycline or tetracycline, 13.
Concurrent malignancy other than melanoma and/or history of malignancy other
than
melanoma within 3 years of date of first planned dose of REGN2810, except for
tumors
with negligible risk of metastasis or death, such as adequately treated basal
cell
carcinoma (BCC) of the skin, carcinoma in situ of the cervix, or ductal
carcinoma in situ
of the breast, or history of prostate adenocarcinoma treated with curative
intent at least
3 years prior and with undetectable PSA for at least 3 years prior to
enrollment. Patients
with hematologic malignancies (e.g., chronic lymphocytic leukemia, CLL) are
excluded., 14. Any acute or chronic psychiatric problems that, in the opinion
of the investigator, make
the patient ineligible for participation., 15. Patients with a history of solid
organ transplant., 16. Any medical co-morbidity, clinical laboratory finding,
or concomitant medication that, in the opinion of the investigator, renders the
patient an unsuitable candidate for tumor biopsies due to high safety risks.,
17. Any medical co-morbidity, physical examination finding, or metabolic
dysfunction, or clinical laboratory abnormality that, in the opinion of the
investigator, renders the patient unsuitable for participation in a clinical
trial due to high safety risks and/or potential to affect interpretation of
results of the study., 18. Inability to undergo any response assessment by
contrast-enhanced radiologic imaging., 19. Pregnant or breastfeeding women, 20.
Sexually active men or women of childbearing potential who are unwilling to
practice
highly effective contraception prior to the initial dose, during the study, and
for at least 6
months after the last dose. , 21. Prior treatment with idelalisib, 22.
Radiation therapy within 2 weeks prior to enrollment and not recovered to
baseline from
any AE due to radiation., See protocol section 6.2.2. for more detailed
information
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 | EUCTR2016-002755-16-NL |
| CCMO | NL59275.091.16 |