Primary ObjectiveThe primary objective is to assess safety and tolerability, describe the dose limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or the maximum administered dose (MAD; in the absence of exceeding the MTD) for…
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Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is safety as assessed by presence of adverse event (AE),
serious adverse event (SAE), DLT, abnormal laboratory parameter, vital sign,
and electrocardiogram results.
Secondary outcome
Secondary Endpoints
1. The endpoints for assessment of antitumor activity include best overall
response, objective response (OR), disease control (DC), duration of response
(DoR), progression-free survival (PFS), and overall survival (OS), and the
percent change from baseline in target lesion sum of diameters. RECIST Version
1.1 will be used for assessment of tumor response.
2. The endpoints for assessment of PK of MEDI0562, durvalumab, and tremelimumab
include individual MEDI0562, durvalumab, and tremelimumab concentrations at
different time points after administration. PK parameters that may be modeled
on these data include, but are not limited to, maximum observed concentration,
area under the concentration-time curve, clearance, and terminal half-life.
3. The endpoints for assessment of immunogenicity of MEDI0562, durvalumab, and
tremelimumab include the number and percentage of subjects who develop
detectable antidrug antibodies.
4. The endpoints for assessment of pharmacodynamic activity include induction
of Ki67 on peripheral cluster of differentiation (CD)4+ and CD8+ memory T-cell
populations and assessment of tumor-infiltrating lymphocytes (TILs) in tumor
biopsy specimens.
Background summary
The importance of the immune system in cancer development and progression has
been recognized during the past decade (Hanahan and Weinberg, 2000). Failure of
immune surveillance of pre-neoplastic lesions and micro-metastases is a key
step in cancer development. Chronically immunosuppressed individuals show
higher rates of cancer. This observation led to the hypothesis that sporadic
cancers among immunocompetent individuals are likely to be minimally
immunogenic, allowing for passive escape from immune surveillance. Recent data
suggests that this may be an oversimplification. Some sporadic tumors are
highly immunogenic, but actively suppress the local immune environment through
production of immunosuppressive cytokines (Shields et al, 2010). As such, the
local tumor environment is likely a highly dynamic environment where most
tumors grow and metastasize through adaptive responses that modulate antitumor
immunity.
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth
of many types of cancer (Gooden et al, 2011). Most tumors show infiltration by
TILs, but tumors modulate the local microenvironment through expression of
inhibitory molecules. Engagement of TIL cell-surface receptors with these
inhibitory ligands leads to a dysfunctional immune response, causes T cell
exhaustion, and facilitates tumor progression (Baitsch et al, 2012; Crespo et
al, 2013). Novel monoclonal antibodies (mAbs) that block these inhibitory
receptors have shown significant clinical activity across a number of tumor
types (Wolchok et al, 2009; Hodi et al, 2010; Robert et al, 2011; Brahmer et
al, 2010; Topalian et al, 2012). Specifically, blockade of immune-checkpoint
inhibitors cytotoxic T lymphocyte-associated antigen 4 (CTLA 4), programmed
death 1 (PD 1), and programmed death ligand 1 (PD L1) have shown clinical
activity not only in conventionally immune-responsive tumors such as melanoma
(MEL) and renal cell carcinoma (RCC) but also in non small cell lung cancer
(NSCLC); (Brahmer et al, 2010; Brahmer et al, 2012; Topalian et al, 2012;
Gordon et al, 2013); hepatocellular (Sangro et al, 2013), prostate (Harzstark
and Small, 2010; Slovin et al, 2013), and pancreatic (Royal et al, 2010)
cancers; mesothelioma, (Calabro et al, 2013); and other solid tumors (Brahmer
et al, 2010; Brahmer et al, 2012; Gordon et al, 2013).
Study objective
Primary Objective
The primary objective is to assess safety and tolerability, describe the dose
limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or
the maximum administered dose (MAD; in the absence of exceeding the MTD) for
the combination of MEDI0562 and durvalumab or tremelimumab in subjects with
advanced solid tumors.
Study design
This is a Phase 1, multicenter, open-label study of MEDI0562 in combination
with immune therapeutic agents to evaluate the safety, tolerability, PK,
pharmacodynamics, immunogenicity, and antitumor activity in adult subjects with
advanced solid tumors.
The study includes 2 phases, dose escalation and dose expansion, with 2
treatment arms in each phase: MEDI0562/durvalumab combination therapy (Arm A)
and MEDI0562/tremelimumab combination therapy (Arm B). Subjects will remain on
treatment until unacceptable toxicity, progressive disease (PD), or development
of other reason for treatment discontinuation.
Intervention
Up to 6 dose levels of MEDI0562 (2.25, 7.5, 22.5, 75, 225, or 750 mg) via IV
infusion Q2W in combination with either durvalumab (1500 mg) via IV infusion
Q4W (Arm A) or tremelimumab (75, 225, or 750 mg) via IV infusion Q4W for 4
doses only followed by MEDI0562 monotherapy Q2W (Arm B) may be explored.
Study burden and risks
The proposed combination of MEDI0562 with other immune therapeutic agents, such
as durvalumab or tremelimumab, may increase the frequency or severity of
toxicities of the respective individual agents and thus, a Phase 1
dose-exploration study is the appropriate setting to explore the combination of
MEDI0562 with durvalumab or tremelimumab. This study is intended to establish
the MTD or highest protocol defined dose in the absence of an MTD and the
safety profile of MEDI0562 in combination with immune therapeutic agents. Other
data to be evaluated include the PK, pharmacodynamics, immunogenicity, and
antitumor activity of MEDI0562 combinations. The results from this study will
form the basis for designing future studies.
One Mediimune Way X
Gaithersburg 20878
US
One Mediimune Way X
Gaithersburg 20878
US
Listed location countries
Age
Inclusion criteria
1. Written and signed informed consent and any locally required authorization obtained from the subject/legal representative (where permissible) prior to performing any protocol-related procedures, including screening evaluations.;2. Age * 18 years at the time of study entry.;3.Subjects must have received and have progressed, are refractory, or are intolerant to standard therapy appropriate for the specific tumor type. Subjects should not have received more than 3 prior lines of systemic therapy for recurrent or metastatic disease (including both standard of care and investigational therapies).;4. Subjects in the dose-escalation phase must have histologic documentation of advanced solid tumors, excluding primary CNS tumors and hematologic malignancies.;5. Subjects in the dose-expansion phase must have recurrent or metastatic disease for the
following tumor types based on treatment arm (see protocol);6. During dose escalation, subjects who have received prior therapy with regimens containing CTLA 4, PD L1, or PD 1 antagonists are permitted to enroll if all of the criteria listed in the protocol are met;7. Subjects must have at least 1 lesion that is measurable using RECIST Version 1.1 guidelines ;8. All subjects are encouraged to consent to and provide both pretreatment and on treatment tumor biopsies. If during dose escalation any dose-level cohort is expanded beyond the initial 3 to 6 subjects, the additional subjects enrolled under pharmacodynamic expansion must consent to and undergo both a pre-treatment and an on treatment tumor biopsy. ;9. ECOG Performance score of 0 or 1, with the exception of the UC cohort where an ECOG
performance score of 2 may be permitted
Exclusion criteria
1. Prior treatment with TNFRSF agonists ;2. History of severe allergic reactions to any unknown allergens or any components of the study drug formulations ;3. Active or prior documented autoimmune disease within the past 2 years. ;4. Concurrent enrollment in another clinical study.;5. Receipt of any conventional or investigational anticancer therapy not otherwise specified above within 28 days prior to the first dose of MEDI0562 and durvalumab or tremelimumab combination treatment; in the case of mAbs, 28 days or 5 half lives, whichever is shorter, prior to the first dose of MEDI0562 and durvalumab or tremelimumab combination treatment;6. Any concurrent chemotherapy, IMT, or biologic or hormonal therapy for cancer treatment.;7. Unresolved toxicities from prior anticancer therapy.;8. Systemic therapeutic anticoagulation or daily aspirin dose exceeding 325 mg/per day. ;9. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of MEDI0562. ;10. History of primary immunodeficiency, solid organ transplantation, or tuberculosis;11. Test results indicating active infection with human immunodeficiency virus (HIV) or hepatitis B or C defined by positive serologic testing and confirmatory viral nucleic acid testing .;12. Receipt of live, attenuated vaccine within 28 days prior to the first dose of investigational products ;13. Major surgery (as defined by the investigator) within 4 weeks prior to first dose of MEDI0562 ;14. Other invasive malignancy within 2 years (exception per protocol);15. Uncontrolled intercurrent illness
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 | EUCTR2016-000177-20-NL |
| ClinicalTrials.gov | NCT02705482 |
| CCMO | NL57430.031.16 |