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Mogamulizumab in Combination with Durvalumab or
Tremelimumab in Patients with Advanced Solid Tumors: a Phase I
Study
Authors: Dmitriy Zamarin,1* Omid Hamid,2 Asha Nayak-Kapoor,3 Solmaz
Sahebjam,4 Mario Sznol,5 Agron Collaku,6 Floyd E. Fox,6 Margaret A. Marshall,6 and
David S. Hong7*
Affiliations: 1Memorial Sloan-Kettering Cancer Center, New York, New York, 2The
Angeles Clinic and Research Institute, Los Angeles, California, 3Georgia Cancer
Center, Augusta University, Augusta, Georgia, 4H. Lee Moffitt Cancer Center,
University of South Florida, Tampa, Florida, 5Yale Cancer Center, New Haven,
Connecticut, 6Kyowa Kirin Pharmaceutical Development, Inc., Princeton, New
Jersey, 7MD Anderson Cancer Center, Houston, Texas, USA
Running title: Mogamulizumab Combined with Durvalumab or Tremelimumab
*Co-corresponding Authors: Dmitriy Zamarin, Memorial Sloan-Kettering Cancer
Center, 300 East 66th Street, Room 1313, New York, NY 10065, USA. Phone: 646-
888-2322; Fax: 646-888-4265; E-mail: [email protected] and David S. Hong,
MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX 77030,
USA. Phone: 713-563-5844; Fax: 713-792-0334; E-mail: [email protected]
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Disclosure of Potential Conflicts of Interest
D. Zamarin reports consulting fees from Merck, Synlogic Therapeutics, Western
Oncolytics, Tizona Therapeutics, and Tesaro.
S. Sahebjam reports research support from Merck, Bristol Myers Squibb, and
Brooklyn ImmunoTherapeutics.
M. Sznol reports personal or advisory fees from Intensity Therapeutics,
Adaptimmune, AstraZeneca/MedImmune, Baxalta/Shire, Biodesix, BristolMyers
Squibb, Genentech/Roche, Inovio Pharmaceuticals, Nektar, Lilly, Merck Sharp &
Dohme, Modulate, Molecular Partners, Newlink Genetics, Novartis, Omniox, Pfizer,
Pierre Fabre, Seattle Genetics, Theravance, AcademicCME, DAVAOncology,
Haymarket Media, Physician Education Resource Research to Practice,
Symphogen, Nextcure, Verastem, Innate, Incyte, Iovance, Genmab, Celldex, Abbvie,
Immunocore, Almac, Hinge, Anaeropharma, Array, Biontech, Pieris, Torque, and
Gritstone; and stock options from Actym, Adaptive Biotechnologies, Amphivena,
Nextcure, and Torque.
F.E. Fox is an employee of Kyowa Kirin Pharmaceutical Development, Inc.
A. Collaku and M.A. Marshall are former employees of Kyowa Kirin Pharmaceutical
Development, Inc.
D.S. Hong reports research/grant funding from AbbVie, Adaptimmune, Aldi-Norte,
Amgen, Astra-Zeneca, Bayer, BristolMyers Squibb, Daiichi-Sankyo, Eisai, Fate
Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck,
MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis,
Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; travel,
accommodation, and expenses from LOXO, miRNA, Genmab, AACR, ASCO, and
SITC; consulting or advisory roles for Alpha Insights, Amgen, Axiom, Adaptimmune,
Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack,
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Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza
Therapeutics, and WebMD; and ownership interests in Molecular Match (Advisor),
OncoResponse (Founder), and Presagia Inc. (Advisor).
O. Hamid and A. Nayak-Kapoor report no conflicts of interest.
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Translational Relevance
Mogamulizumab is a monoclonal antibody targeting CCR4, which is highly
expressed by eTregs. This phase I study in advanced solid tumors evaluated
whether depletion of eTregs with mogamulizumab was safe and improved the
efficacy of immune checkpoint inhibitors durvalumab or tremelimumab, targeting PD-
L1 or CTLA-4, respectively. No dose-limiting toxicity occurred with either
combination. No additional efficacy was observed with addition of mogamulizumab
compared to that expected with durvalumab or tremelimumab monotherapy.
Mogamulizumab proof-of-pharmacologic activity was demonstrated by a reduction in
the number of peripheral blood CCR4+ eTregs and intratumoral Tregs; however,
there was no clear correlation of clinical response with reduction in peripheral blood
CCR4+ eTregs or with baseline degree of CCR4+ expression. These observations
suggest that although Treg population depletion by mogamulizumab in combination
with checkpoint inhibitors might be useful in inducing antitumor immunity, it does not
appear to be the only factor sufficient to induce potent antitumor efficacy.
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Abstract
Purpose: The study goal was to determine safety, antitumor activity, and
pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody
(mAb) targeting effector regulatory T cells (eTregs), in combination with mAb
checkpoint inhibitors durvalumab or tremelimumab.
Patients and Methods: This was a multicenter, phase I, dose-escalation study,
followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab
dose escalation proceeded with concurrent dose escalation of durvalumab or
tremelimumab in patients with advanced solid tumors. Cohort expansion occurred
with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg
in patients with advanced pancreatic cancer.
Results: Forty patients were enrolled during dose escalation, followed by 24
patients during dose expansion. No dose-limiting toxicities occurred during dose
escalation. No new or unexpected toxicities were seen. Tolerability, the primary
endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or
tremelimumab 10 mg/kg in the combined dose-escalation and dose-expansion
cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95%
CI: 0.1%, 26.0%) [1 partial response] with each combination treatment. At all doses,
mogamulizumab treatment led to almost complete depletion of peripheral eTregs as
well as reduction of intratumoral Tregs in the majority of patients. There was no clear
correlation of clinical response with peripheral or intratumoral reduction in CCR4+
eTregs or with baseline degree of CCR4+ expression.
Conclusions: Mogamulizumab in combination with durvalumab or tremelimumab
did not result in potent antitumor efficacy in patients with advanced solid tumors.
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Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or tremelimumab
10 mg/kg was acceptable.
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Introduction
Monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4) and programmed cell death 1/programmed cell death ligand 1
(PD-1/PD-L1) immune checkpoints have demonstrated clinical benefit in several
cancer types, although responses have generally been low, limited to a minority of
patients, and are frequently not durable. The combination of checkpoint inhibitors
with immunomodulatory mAbs that act via different mechanisms may offer an
approach to improve therapeutic outcome (1, 2). One potential combination partner
for checkpoint inhibitors might be afforded by an agent that is able to deplete
regulatory T cells (Tregs), given that Tregs play a pivotal role in maintaining
immunological tolerance that can inhibit antitumor immune responses and may
mediate resistance to immunomodulatory therapy targeting CTLA-4 or PD-1/PD-L1
(3–5).
C-C chemokine receptor 4 (CCR4) is a lymphocyte receptor recognizing two
chemokines: CC ligand 17 (CCL17) [also known as thymus and activation-regulated
chemokine (TARC)] and CCL22 [also known as macrophage-derived chemokine
(MDC)] (6). CCR4 is expressed on Th2 cells, various T-cell malignancies, and a
unique effector subset of normal human Tregs (eTregs) (6, 7). CCL17 and CCL22
chemokine production by tumor cells attracts CCR4+ Treg cells into the tumor
microenvironment where they favor tumor escape by suppression of the host
antitumor immune response (8). CCR4 has therefore been suggested as a
therapeutic target. High CCR4+ Treg levels have been detected in a wide range of
murine and human solid tumors, including breast, colorectal, oral squamous,
prostate, lung, renal, hepatic, and ovarian cancer and melanoma and/or have been
associated with tumor progression or metastasis (9–19). Mogamulizumab (KW-
0761), a first-in-class defucosylated humanized anti-CCR4 mAb, was recently FDA-
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approved for adult patients with relapsed or refractory mycosis fungoides or Sézary
syndrome, which are both subtypes of cutaneous T-cell lymphoma (20).
Mogamulizumab has been shown to deplete Tregs from peripheral blood in patients
with solid tumors (21). The combination of mogamulizumab with checkpoint inhibitors
might therefore improve clinical outcomes of patients with advanced malignancies
(21).
Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa (IgG) mAb that
blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1) on immune cells (22, 23).
It is FDA-approved for the treatment of patients with locally advanced or metastatic
urothelial carcinoma and patients with unresectable, Stage III non-small cell lung
cancer (NSCLC) whose disease has not progressed following concurrent platinum-
based chemotherapy and radiation therapy.
Tremelimumab (CP-675,206) is a human IgG2 mAb directed against CTLA-4
cluster of differentiation (CD152), a cell surface receptor that is expressed primarily
on activated T cells and acts to inhibit their activation, that is undergoing clinical
investigation. Tremelimumab blocks the interaction of CTLA-4 with CD80 and CD86,
resulting in increased release of cytokines from human T cells (24). This blockade
markedly enhances T-cell activation and antitumor activity in animal models,
including killing of established murine solid tumors and induction of protective
antitumor immunity (24). Tremelimumab has demonstrated activity in clinical trials of
patients with hepatocellular carcinoma as monotherapy (25) and in combination with
durvalumab in malignant mesothelioma (26).
The aim of the present clinical study was to evaluate whether CCR4+ Treg
depletion by mogamulizumab enhances antitumor response in combination with the
checkpoint inhibitors durvalumab or tremelimumab in patients with advanced solid
tumors.
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Materials and Methods
Patients
Eligible patients included adult patients (≥18 years) with measurable, histologically
or cytologically confirmed locally advanced or metastatic solid tumors that had been
previously treated and for which no additional standard or approved therapy options
were available. They had to have adequate organ and bone marrow function,
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and a life
expectancy >3 months. Detailed inclusion/exclusion criteria are provided as
Supplementary Information. Advice on standard restrictions to avoid pregnancy was
given to female patients of child-bearing potential and to male patients with a partner
of child-bearing potential.
Study design and objectives
This was a two-part, multicenter, Phase I open-label, dose-escalation, cohort-
expansion study of mogamulizumab + durvalumab (Arm A) and mogamulizumab +
tremelimumab (Arm B) in adults with locally advanced or metastatic solid tumors.
Part 1 had a parallel 3+3 design to identify the maximum tolerated dose (MTD) or the
highest protocol-defined dose in the absence of MTD for each combination. That
dose level was used for cohort expansion in Part 2.
The dose-escalation period followed the standard 3+3 design. Patients who did
not receive all infusions in Cycle 1 at the assigned doses or did not complete safety
follow-up (until 1 week after end of Cycle 1) were replaced. The doses administered
with the two treatments are summarized in Table 1. In the initial study protocol, three
dose levels were planned for each treatment (Cohorts 1A–3A and 1B–3B) to
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establish the recommended dose level for cohort expansion, which in actuality
occurred at the highest dose level for each combination treatment (Cohorts 5A and
5B). Following protocol amendment, an additional, higher dose-escalation cohort
was added for each treatment (Cohorts 4A and 4B) after cohort expansion was
completed in Cohorts 5A and 5B. Expansion of Cohorts 4A and 4B was only planned
for ≥2 responses in either cohort, which would have provided an 80% chance of a
true objective response rate (ORR) of the treatment >14%.
During cohort expansion in the initial protocol, it was intended to recruit patients
with pancreatic cancer, NSCLC, or head and neck cancer as consecutive disease
strata (12 patients per tumor type). Following the dose escalation, a decision was
made to first recruit patients with pancreatic cancer to the expansion Cohorts 5A and
5B, after which the trial was stopped. Study termination was considered after ORR
was evaluated for the first 12 patients in each expansion cohort. The study used an
efficacy cut-off for which there was an 80% chance that the true ORR was >20% for
the mogamulizumab + durvalumab combination and >15% for the mogamulizumab +
tremelimumab combination. A stop to cohort expansion would also have been
considered if the proportion of patients with dose-limiting toxicity (DLT) became
statistically significant (>16.7%) with either treatment combination.
The primary objective was to characterize the safety and tolerability, and to
determine the MTD of the combinations of mogamulizumab + durvalumab and
mogamulizumab + tremelimumab in patients with advanced solid tumors. Secondary
objectives were to evaluate the clinical activity of the combinations and to evaluate
the pharmacokinetics and immunogenicity of mogamulizumab, durvalumab, and
tremelimumab. An exploratory objective was to determine the pharmacodynamic
profile of the combinations and whether any biomarkers were correlated with safety
or activity.
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Study drug administration
The drug combinations used in this study had not been previously administered in
humans. Lower-than-approved doses were therefore used to start dose escalation.
The rationale for dose selection is elaborated in more detail as Supplementary
Information.
Treatment cycles were 28 days. Mogamulizumab (0.3, 1, and 3 mg/kg) was
administered by intravenous (IV) infusion over ≥1 hour on Days 1, 8, 15, and 22 of
the Cycle 1 and on Days 1 and 15 of each subsequent cycle. Mogamulizumab
3 mg/kg was administered over ≥3 hours for the first infusion. If well-tolerated,
subsequent infusions could be administered over 1.5 hours. A minimum 1-hour post-
dose observation period was required after each infusion. After the 1-hour
mogamulizumab observation period, durvalumab (3 and 10 mg/kg) was administered
by IV infusion over ≥1 hour on Days 1 and 15 of each cycle. After the 1-hour
mogamulizumab observation period, tremelimumab (3 and 10 mg/kg) was
administered by IV infusion over ≥1 hour on Day 1 of each cycle for the first six
cycles and then every 12 weeks. A minimum 4-hour post-dose observation period
was required after the first two infusions of durvalumab or tremelimumab, which was
reduced to a minimum of 1 hour after subsequent infusions. All infusions were made
using an infusion pump with a 0.22- or 0.2-µm inline filter. Mogamulizumab +
durvalumab was administered for up to 12 months and mogamulizumab +
tremelimumab for up to 24 months.
Patients were premedicated with oral acetaminophen and IV diphenhydramine
50 mg (or equivalent) prior to the first mogamulizumab infusion. If a patient
experienced an infusion-related reaction, pre-medication was recommended prior to
subsequent infusions.
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Concurrent treatments that were prohibited during the study are detailed as
Supplementary Information.
Definition of dose-limiting toxicity
DLT was determined from the first dose until 1 week after the last dose of Cycle 1.
DLTs were defined as: any adverse event (AE) Grade ≥4 (except for Grade 4
neutropenia not associated with fever or systemic infection that improved by ≥1
grade within 3 days or Grade 4 lymphopenia); Grade ≥3 non-infectious pneumonitis,
colitis, or febrile neutropenia; any Grade 3 immune-mediated AE that did not
downgrade to Grade 2 within 3 days despite optimal management or did not
downgrade to Grade ≤1 or baseline within 14 days; liver transaminase elevation >8
times the upper limit of normal (ULN) or total bilirubin >5 times ULN; Grade 2
pneumonitis that did not resolve to Grade ≤1 within 3 days of starting maximal
supportive care; and Stevens-Johnson syndrome or toxic epidermal necrolysis. This
excluded any AEs clearly and directly related to the primary disease or to another
etiology. More detailed DLT definitions are provided as Supplementary Information.
Assessments
Demographics and medical/cancer history were recorded at screening (up to 4
weeks prior to first dose). Vital signs were recorded at every visit. Physical
examination was undertaken at screening and at end of treatment. Hematology
profile was determined at screening, on Days 1, 8, 15, 22, and 22 of Cycle 1, on
Days 1 and 15, of Cycles ≥2, and at end of treatment. Serum chemistry profile was
determined at screening, on Days 1, 8, 15, 22, and 22 of Cycle 1, on Day 1 of Cycles
≥2, and at end of treatment. Urinalysis was undertaken at screening, on Days 1 and
15 of Cycle 1, on Day 1 of Cycles ≥2, and at end of treatment. Coagulation profile
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and 12-lead ECG were performed at screening, on Day 1 of Cycles ≥1, and at end of
treatment. Thyroid function testing was undertaken at screening, on Day 1 of Cycles
≥2, and at end of treatment. ECOG performance status was determined at screening,
on Day 1 of Cycle 1, and end of treatment. Virus testing was performed at screening.
Serum pregnancy testing was undertaken at screening and urinary pregnancy
testing was performed on Day 1 of Cycles ≥1, and at end of treatment in women of
child-bearing potential.
Tumor response and safety
Tumor assessment was performed at screening and every 2 cycles in the first
year and every 3 cycles in the second year using Response Evaluation Criteria in
Solid Tumors (RECIST) v1.1 criteria (27). Evaluation included serum tumor markers
applicable to a patient's tumor type. ORR was determined for the percentage of
patients with either complete response (CR) or partial response (PR) confirmed ≥4
weeks later. Patients who did not meet CR/PR were classified as stable disease
(SD) if assessed as SD (or better) ≥6 weeks after first dose of investigational
medicinal product (IMP).
Adverse events (AEs) were recorded following observation by the investigator or
in response to non-leading questioning during clinic visits, after spontaneous
reporting by the patient, or on the basis of clinical or laboratory tests. AEs were
graded by National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI-CTCAE) v4.03 and classified by the investigator with respect to
relationship to treatment (definitely, probably, possibly, or unrelated). Treatment-
related AEs included those considered definitely, probably, or possibly related to
treatment. Serious AEs (SAEs) were reported in an expedited manner. Safety was
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analyzed in the safety analysis set that included all patients who received at least
one dose (even a partial dose) of IMP.
Antidrug antibody (ADA) testing was undertaken for mogamulizumab in each
combination arm using blood samples pre-dose at the start of Cycles 1–5 and 90
days after the end of treatment. Samples were also taken for ADA testing for
durvalumab and tremelimumab but were not analyzed as the study was terminated
early.
Biomarker assessments
Blood samples were taken for biomarker and pharmacodynamic assessment pre-
dose on Days 1 and 15 of Cycle 1, pre-dose at the start of Cycles 2–5 and the last
cycle, and 90 days after the end of treatment. The main biomarker parameters to be
measured included circulating CCR4+ Tregs, activated T-cell populations, and other
immune cell populations by flow cytometry and immunohistochemtistry. For flow
cytometry, the following antibody probes were used: CD3 V510; clone 510
(BioLegend, San Diego, CA), CD4 PECy7; clone SK3 (BD), CCR6 APC; clone
G034E3 (BioLegend), CD183 PerCPCy5.5; clone G025H7 (BioLegend), CCR10 PE;
clone 6588-5 (BioLegend), CCR5 FITC; clone J418F1 (BioLegend), CTLA-4 APC;
clone BNI3 (BD), CD8 V421; clone SK1 (BioLegend), PD-1 PerCPCy5.5; clone
EH12.1 (BD), Ki67 PE; clone Ki-67 (BioLegend), CD45 FITC, CD69 APC, ICOS PE,
CD38 PerCPCy5.5, CD45 FITC; clone HI30 (BioLegend), CCR6 APC; clone 53103
(R&D Systems), CCR5 FITC: clone 2D7 (BD), CCR10 PE: clone 1B5 (BD), CCR4
V421; clone 1G1 (BD), and CD183 PerCPCy5.5; clone G025H7 (BioLegend). Briefly,
for surface staining, whole blood was added to fluorochrome-conjugated monoclonal
antibodies and incubated at room temperature. Samples were lysed and washed
once with 1× Dulbecco's phosphate-buffered saline (DPBS). Samples were
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resuspended in 1× DPBS for acquisition on the flow cytometer. For flow cytometric
intracellular staining, whole blood was added to fluorochrome-conjugated
monoclonal surface antibodies and incubated at room temperature. Samples were
lysed and washed once with 1× DPBS. Samples were washed again with 1×
permeabilization buffer (perm buffer) and then resuspended in 1× perm buffer with
intracellular antibody(s). Samples were incubated at room temperature and washed
twice with 1× perm buffer. Samples were resuspended in 1× DPBS for acquisition on
the flow cytometer. For CCR4/FoxP3 staining, whole blood was washed in Stain
Buffer (BSA) and then added to fluorochrome-conjugated monoclonal surface
antibodies for 1 hour at 2–8°C. Samples were lysed and washed once with Stain
Buffer. Samples were fixed and permeabilized using the FoxP3 Buffer Kit (BD)
according to the manufacturer's instructions. Samples were then resuspended in
Stain Buffer along with FoxP3 or isotype control. Samples were incubated at room
temperature and then washed twice with Stain Buffer. Samples were resuspended in
Stain Buffer for acquisition on the flow cytometer.
Fluorescence immunohistochemistry (F-IHC) staining for CCR4 and other cell
markers was undertaken for tumor biopsy samples taken at baseline and at the end
of Cycle 2 or Cycle 4. The following antibodies were used: polyclonal anti-CCR4
(Sigma Life Science), CD25; clone SP176 (Novus), anti-FOXP3; clone D2W8E (Cell
Signaling Technologies, anti-CD16; clone 0.N.82 (Abcam), CD56 and anti-PD1;
clone NAT105 (Biocare Medical), and anti-CD4; clone 4B12, anti-CD8; clone
C8/144B, and polyclonal rabbit anti-cytokeratin, wide spectrum screening (DAKO). F-
IHC was performed as previously described by (28). Briefly, slide-mounted, formalin-
fixed, paraffin-embedded tumor biopsy slices were dewaxed and used for staining
using an automated Vectra 2 Intelligent Slide Analysis System (Perkin Elmer,
Waltham, MA) (29) to examine tissue regions of interest. Tumor regions of interest
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were identified by the presence of cytokeratin or S100 depending on the tissue types.
Imaging analysis was performed by fully automated AQUA Technology (Perkin-
Elmer).
Statistical analysis
No formal sample size calculation was performed for this study. Part 1 of the
study for each combination utilized a standard 3+3 design in four cohorts. In Part 2,
an additional 36 patients were intended to be recruited in the dose-expansion cohort
of each combination treatment.
Demographic, baseline characteristics, and efficacy and safety endpoints were
summarized descriptively. Frequency and percentages were used for categorical
variables and summary statistics (number, mean, standard deviation [SD], median,
minimum, and maximum) were calculated for continuous variables.
Efficacy endpoints were analyzed using the efficacy analysis set which included
all patients who had measurable disease and completed the first cycle of
combination therapy and who had baseline and at least one post-baseline on-study
assessment for response. ORR, progression-free survival (PFS), and overall survival
(OS) were reported in patients in the dose-escalation cohort plus the dose-expansion
cohort who were treated with the same dose regimen of mogamulizumab 1 mg/kg +
durvalumab 10 mg/kg (Cohorts 3A and 5A) and mogamulizumab 1 mg/kg +
tremelimumab 10 mg/kg (Cohorts 3B and 5B). Two-sided 95% exact confidence
interval (CI) for the ORR was derived using the Clopper-Pearson exact binomial
method (30). Duration of response, PFS, and OS were defined conventionally, and
median values, along with two-sided 95% CI (31), were estimated using the Kaplan-
Meier method.
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Ethics
The study was conducted in accordance with the Declaration of Helsinki and
International Conference for Harmonization of Good Clinical Practice Guidelines.
The protocol and its amendments were approved the local institutional review boards
at the participating centers. All patients provided written informed consent prior to
study registration. The study was registered in ClinicalTrials.gov (NCT02301130).
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Results
Patient characteristics
The study was conducted between 26 November 2014 and 5 March 2018 at 7 US
centers (MD Anderson Cancer Center, Houston, TX; The Angeles Clinic and
Research Institute, Los Angeles, CA; Smilow Cancer Hospital, New Haven, CT;
Memorial Sloan Kettering Cancer Center, New York, NY; UCLA Hematology and
Oncology Clinic, Los Angeles, CA; Georgia Cancer Center, Augusta, GA). A total of
64 patients were enrolled and treated: Part 1 (n = 40) and Part 2 (n = 24). Baseline
clinical and demographic characteristics of the patients are summarized in Table 2.
Patients recruited to the dose-expansion cohorts had pancreatic cancer exclusively.
All patients were included in the safety analysis set, which included all patients
who received treatment. One patient receiving mogamulizumab + durvalumab was
not evaluated for efficacy because of lack of post-baseline assessment. Patient
disposition during the study is detailed as Supplementary Information (Fig. S1).
Reasons for discontinuation from the study were progressive disease (n = 36),
adverse events (n = 9), consent withdrawal (n = 5), and lost to follow-up (n = 2);
three patients completed treatment. Drug exposure for the different cohorts is
detailed as Supplementary Information (Tables S1–S4). Median relative dose
intensity for mogamulizumab, durvalumab, and tremelimumab was essentially 100%
across cohorts (99.3%–100.6%; range, 95.6%–102.7%).
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Dose-limiting toxicity and safety
No DLTs occurred in any patients in the dose-escalation cohorts with either
combination treatment. Cohort expansion therefore occurred with mogamulizumab
1 mg/kg + durvalumab 10 mg/kg and mogamulizumab 1 mg/kg + tremelimumab
10 mg/kg, i.e. the highest intended dose in the original protocol based on maximum
pharmacodynamic effect (defined by CCR4+ Treg depletion) achieved with
mogamulizumab 1 mg/kg. The higher dose cohorts 4A and 4B (with mogamulizumab
3 mg/kg in each combination) were added by protocol amendment after cohort
expansion had started in Cohorts 5A and 5B.
The most common and all Grade ≥3 treatment-related AEs in the same-dose
cohorts (dose escalation + cohort expansion) for each combination treatment are
shown in Table 3. The most common and AE Grade ≥3 treatment-related AEs were
maculopapular rash for both treatment arms: mogamulizumab 1 mg/kg + durvalumab
10 mg/kg (36.8% and 21.1%, respectively) and mogamulizumab 1 mg/kg +
tremelimumab 10 mg/kg (26.3% and 10.5%, respectively). Over the whole study
(dose-escalation and dose-expansion phases), five patients died during the study in
the mogamulizumab + durvalumab arm and two in the mogamulizumab +
tremelimumab arm, none of which were related to the study treatments. In the same-
dose cohorts (dose escalation + dose-expansion), SAEs occurred in 16 of 19
(84.2%) of patients in the mogamulizumab 1 mg/kg + durvalumab 10 mg/kg arm and
in 10 of 19 (52.6%) in the mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg arm,
of which six (31.6%) and two (10.5%), respectively, were considered related to
treatment. Discontinuation of any IMP due to treatment-emergent AEs occurred in
six (31.6%) patients in the mogamulizumab 1 mg/kg + durvalumab 10 mg/kg arm
and in two (10.5%) patients in the mogamulizumab 1 mg/kg + tremelimumab
10 mg/kg arm. Details for AEs of special interest are detailed as Supplementary
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Information. There were no unanticipated laboratory safety signals or any consistent
or clinically meaningful differences between the groups in vital signs, physical
examinations, or ECG parameters with either combination treatment. One patient
developed anti-mogamulizumab antibodies (not neutralizing) while receiving
mogamulizumab + tremelimumab, which became negative at 90 days after the end
of treatment.
Antitumor activity
Efficacy (as ORR and OS) were evaluated in patients in the dose-escalation
cohort plus the dose-expansion cohort who were treated with the same dose
regimen of mogamulizumab 1 mg/kg + durvalumab 10 mg/kg (Cohorts 3A and 5A)
and mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg (Cohorts 3B and 5B)
[Table 5]. ORR was the same in both treatment groups, 5.3% (95% CI: 0.1, 26).
There was only one patient with PR in each of these two treatment groups. Each of
the patients with PR occurred in the dose-escalation cohorts. The duration of
response was 10.6 months for a patient with alveolar soft part sarcoma in the
mogamulizumab 1 mg/kg + durvalumab 10 mg/kg arm and 3.7 months for a patient
with prostate cancer in the mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg arm.
Five (26.3%) patients in the mogamulizumab 1 mg/kg + durvalumab 10 mg/kg arm
and 7 (36.8%) patients in the mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg
arm had SD. The median OS of patients in the mogamulizumab 1 mg/kg +
durvalumab 10 mg/kg arm was 8.9 months (95% CI: 4.3, 18.4) and that for patients
in the mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg arm was 4.4 months
(95% CI: 2.5, 13.4). The OS curves are presented in Supplementary Information
(Fig. S2). Both treatments had similar response survival function. However, the
survival estimate in the mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg arm
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drops rapidly after 3 months, while that for mogamulizumab 1 mg/kg + durvalumab
10 mg/kg arm drops after a longer time period of about 9 months. No responses
occurred with either combination treatment during dose-expansion in the patients
with pancreatic cancer. The stop criterion for further expansion was therefore
reached. Additionally, there was a strategic decision to not expand into head and
neck or lung tumor types; PD-1/checkpoint blockade had been generally adopted as
a standard of care for these tumor types during the course of this trial, making
accrual of patients with those tumor types problematic. The changes in tumor burden
over time for each treatment combination are shown as spider plots in
Supplementary Information (Figs S3 and S4).
Besides the two patients with a PR response observed in the efficacy data set
with the same dose regimen of mogamulizumab 1 mg/kg + tremelimumab 10 mg/kg
and mogamulizumab 1 mg/kg + durvalumab 10 mg/kg, one additional patient with
renal cell carcinoma in the dose-escalation cohort of mogamulizumab 3 mg/kg +
durvalumab 10 mg/kg had a PR. None of the patients with a PR response had prior
treatment with an immune checkpoint inhibitor. Five patients had received prior PD-
1/PD-L1 blockade and were enrolled in the mogamulizumab + tremelimumab
cohorts. Two of the patients (both with renal cell carcinoma) demonstrated SD as
best response, while the remaining patients (1 with NSCLC and 2 with colorectal
cancer) had PD.
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Pharmacodynamics
Biomarker assessment on the study included quantification of the Tregs and other
immune cell populations in peripheral blood and tumors. Various Treg populations in
peripheral blood were defined as previously (7, 32). There was no apparent
therapeutic relationship between clinical response of patients in both combination
treatment arms and the degree of baseline CCR4+ expression on various T-cell
subsets, including CD4, CD8, naive Tregs (CCR4+CD45RA+FoxP3lo), eTregs
(CCR4+CD45RA–FoxP3hi), and non-suppressor Tregs (CD4+CD45RA–FoxP3lo) (Fig.
1A). Therapy with mogamulizumab resulted in reduction of peripheral blood CCR4+
eTregs in both combination treatment arms at all dose levels, with maintenance of
depletion throughout treatment (Fig. 1B). Assessment of other cell populations
revealed concomitant general depletion of CCR4+CD4 (Fig. 1C) and CCR4+CD8
lymphocytes (Fig. 1D). Reductions in natural killer, Th2, Th17, and Th22 cells were
also seen (Supplementary Information, Table S5). There did not appear to be
correlation between clinical response and the depletion of CCR4+ eTreg,
CCR4+CD4, or CCR4+CD8 populations (Fig. 1B–D). Analysis of CD8 T-cell
activation markers in peripheral blood, such as CD38, CD69, CD134, and HLA-DR
demonstrated evidence of T-cell activation in response to therapy in some patients;
however, this did not correlate with response (Supplementary Information, Fig. S5).
In patients in whom pre- and on-treatment biopsies could be performed and
yielded sufficient tissue, quantification of Tregs and other immune cell subsets in
tumor microenvironment was performed using F-IHC. In the majority of the analyzed
cases, there was a relative reduction of tumor-infiltrating Tregs such as
CCR4+FoxP3+ and CD25+FoxP3+ in response to therapy to a varying degree (Fig.
2A-B). There were no consistent trends in other cell populations, including overall
CD4+ lymphocytes, CD8+ lymphocytes, or NK cells (CD16+CD56+). Similar to
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peripheral blood findings, changes in the intratumoral immune cell populations,
including the degree of Treg depletion, did not appear to correlate with clinical
response. There was not sufficient tissue remaining to perform PD-L1 testing or
genetic analyses such as tumor mutational burden.
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Discussion
Regulatory T cells play a major immunosuppressive role in the tumor
microenvironment and may represent a major obstacle to the efficacy of cancer
immunotherapies (33). Across cancer types, Treg infiltration is associated with poor
outcomes (34). Studies in preclinical models have indicated that depletion of Tregs
may afford therapeutic benefit, particularly when used in combination with other
interventions, such as radiation or immune checkpoint blockade (35, 36).
Therapeutic depletion of Tregs, however, has been limited by a lack of unique
surface marker that is not expressed on effector T-cell populations. For example, the
initial enthusiasm for targeting of Tregs with the anti-CD25 antibody daclizumab was
dampened due to its concomitant depletion of activated effector T cells (37–39).
Recent studies, however, have demonstrated that modification of the Fc portion of
the anti-CD25 antibody to bind the inhibitory Fc gamma receptor in tumors can
enhance its anti-tumor activity (40).
CCR4 is highly and predominantly expressed on the population of regulatory T
cells that have been shown to possess the most potent immunosuppressive activity.
Prior studies have demonstrated that mogamulizumab could potently deplete
peripheral blood CCR4+ Tregs (7, 21). Mogamulizumab has been engineered with a
defucosylated Fc region with enhanced ability for ADCC due to more efficient Fc
gamma receptor binding (41), thus making it an attractive candidate for intratumoral
T-cell depletion.
Despite the reasonable therapeutic rationale for combinatorial therapy of
mogamulizumab with immune checkpoint blockade, the current clinical trial suggests
that although Treg population depletion by mogamulizumab in combination with
checkpoint inhibitors might be useful in inducing antitumor immunity, it does not
appear to be the only factor sufficient to induce potent antitumor efficacy as ORR
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was 5.3% (95% CI; 0.1%, 26.0%) in each treatment arm (mogamulizumab 1 mg/kg
in combination with durvalumab 10 mg/kg or tremelimumab 10 mg/kg). In addition,
no further expansion was pursued in the cohorts containing mogamulizumab
3 mg/kg given the lack of any objective responses in these cohorts. Prior studies with
mogamulizumab in solid tumors noted evidence of single-agent clinical activity of this
drug (21). While several patients on our study developed durable responses, it is not
possible to conclude whether the clinical activity could be attributed to
mogamulizumab or its immune checkpoint inhibitor partner. Results of a Phase I
study of mogamulizumab in combination with the anti-PD-1 antibody, nivolumab, in
90 patients with advanced or metastatic solid tumors have recently been published
[42]. The safety profile was acceptable and similar to that in the present study. ORR
across all tumor types was 12%. ORR was 7% among the 15 patients with
pancreatic adenocarcinoma, which is similar to the present study. Higher ORR was
reported in 15 patients with non-small cell lung cancer (20%) and in 15 patients with
hepatocellular carcinoma (27%). Interestingly, in the current study, a response was
observed in prostate cancer, which is considered an immunologically “cold” tumor.
While CCR4+ regulatory T cells have been shown to be associated with poor
prognosis in prostate cancer (43), there is evidence of response of prostate cancer
to single-agent CTLA-4 blockade (44, 45). Thus, it is unclear whether our responding
patient could have benefitted from tremelimumab alone, or whether addition of
mogamulizumab was beneficial.
With respect to safety, the primary endpoint, the combination of mogamulizumab
with either durvalumab or tremelimumab proved tolerable in the treatment of patients
with solid tumors. AEs were manageable and generally mild to moderate in intensity.
No DLTs occurred in the dose-escalation cohorts and no MTD was established with
the tested doses of mogamulizumab up to 3 mg/kg in combination with durvalumab
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or tremelimumab 10 mg/kg. The most common treatment-related AEs included
maculopapular rash, fatigue, pruritus, infusion-related reactions, and diarrhea. The
most common treatment-related AEs grade ≥3 were maculopapular rash, pruritus,
and colitis. The overall AE profiles including AEs of special interest during the
combination treatments are similar to those previously reported with mogamulizumab
(20, 46), durvalumab (47, 48), or tremelimumab (49–51) monotherapy. No new
safety concerns were identified with either combination treatment.
The study was stopped early since it had already accumulated sufficient safety
data (primary objective); therefore, there was no need to continue to collect more
once it was apparent that there was no apparent efficacy (secondary objective). Due
to this study stop, it was decided to undertake no analysis of pharmacokinetic data,
which had been another secondary endpoint of the study. In addition, analyses of
pharmacokinetic/pharmacodynamic interactions and exposure/response relationship
were not undertaken. Exploratory pharmacodynamic analyses are still warranted as
potentially meaningful to undertake.
Mogamulizumab proof-of-pharmacologic activity was demonstrated by a reduction
in the number of CCR4+ eTregs, as seen in other studies of mogamulizumab
monotherapy in patients with solid tumors (7). Depletion of CCR4+ eTregs or
differentiated CD4 T cells appeared relatively constant when increasing
mogamulizumab dose over the range from 0.3 to 3 mg/kg. Similarly, reduction of
intratumoral Tregs to a varying degree was observed in the majority of the patients
from whom pre- and on-treatment tissue was available; however, there was no
apparent correlation between Treg reduction and clinical response. Similarly, a
correlation between baseline CCR4+ expression and clinical response could not be
established due to small numbers of patients with response.
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We suspect that there are several reasons for why marked depletion of CCR4+
Tregs was achieved in peripheral blood, but not in tumors and why therapeutic
enhancement of combination therapies was not seen. First of all, it is unclear how
much antibody was actually able to penetrate the tumors. Second, depletion of Tregs
by mogamulizumab is likely dependent on presence of cells expressing activating Fc
receptors, such as NK cells (via antibody-dependent cell-mediated cytotoxicity) and
possibly phagocytes. Absence of these additional cell populations from the tumor
microenvironment could potentially limit the efficacy of mogamulizumab, even when
the drug is present in sufficient quantities. Third, in peripheral blood, we observed
significant depletion of non-eTreg T-cell populations, both in the CD4+ and CD8+ T-
cell compartments. It is thus possible that concomitant depletion of effector T-cell
populations could negatively offset the therapeutic effect afforded by Treg depletion.
Fourth, it is unknown whether Tregs play a key immunosuppressive role in the
cancer types evaluated in the study. Lastly, the majority of the patients in the study
had advanced solid tumors such as pancreatic cancer that typically do not respond
to immune checkpoint blockade and it is likely that targeting of additional
mechanisms of immunosuppression would be necessary to achieve therapeutic
efficacy in these patients.
In conclusion, the efficacy of durvalumab or tremelimumab was not enhanced by
the addition of mogamulizumab in patients with advanced solid tumors despite
achieving significant depletion of eTregs in both peripheral blood and tumor. It is
likely that peripheral eTreg depletion alone is not sufficient to reverse the
immunosuppressive effect driving therapeutic resistance to immune checkpoint
blockade. Further research into the strategies to enhance depletion of Tregs using
combinations of mogamulizumab with other strategies may be warranted.
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Acknowledgments
This study was sponsored by Kyowa Kirin Pharmaceutical Development, Inc. D.
Zamarin is funded in part by the MSK Cancer Center Support Grant of the National
Institutes of Health/National Cancer Institute (P30CA008748). Medical writing and
editorial support was provided by P.A. Todd of Tajut Ltd. (Kaiapoi, New Zealand),
and S.E. Johnson of S. E. Johnson Consulting, LLC (New Hope, PA), which was
funded by Kyowa Kirin Pharmaceutical Development, Inc. (Princeton, NJ).
Authors' Contributions
Conception and design: M.A. Marshall
Development of methodology: F.E. Fox
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): D. Zamarin, O. Hamid, A. Nayak-Kapoor, S. Sahebjam, M.
Szbol, F.E. Fox, D.S. Hong
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): A. Collaku, F.E. Fox
Writing, review, and/or revision of the manuscript: D. Zamarin, O. Hamid, A.
Nayak-Kapoor, S. Sahebjam, M. Szbol, A. Collaku, F.E. Fox, M.A. Marshall, D.S.
Hong
Administrative, technical, or material support (i.e., reporting or organizing
data, constructing databases: F.E. Fox
Study supervision: F.E. Fox, M.A. Marshall
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36
Tables
Table 1. Doses administered in the dose-escalation and dose-expansion cohorts
and number of patients enrolled
Mogamulizumab (Moga) + Durvalumab (Durva)
Cohort 1A (n = 4)
[dose-escalation]
Cohort 2A (n = 3)
[dose-escalation]
Cohort 3A (n = 7)
[dose-escalation]
Cohort 4A (n = 7)
[dose-escalation]
Cohort 5A (n = 12)
[dose-expansion]
Moga 0.3 mg/kg +
Durva 3 mg/kg
Moga 1 mg/kg +
Durva 3 mg/kg
Moga 1 mg/kg +
Durva 10 mg/kg
Moga 3 mg/kg +
Durva 10 mg/kg
Moga 1 mg/kg +
Durva 10 mg/kg
Mogamulizumab (Moga) + Tremelimumab (Treme)
Cohort 1B (n = 3)
[dose-escalation]
Cohort 2B (n = 3)
[dose-escalation]
Cohort 3B (n = 7)
[dose-escalation]
Cohort 4B (n = 6)
[dose-escalation]
Cohort 5B (n = 12)
[dose-escalation]
Moga 0.3 mg/kg +
Treme 3 mg/kg
Moga 1 mg/kg +
Treme 3 mg/kg
Moga 1 mg/kg +
Treme 10 mg/kg
Moga 3 mg/kg +
Treme 10 mg/kg
Moga 1 mg/kg +
Treme 10 mg/kg
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37
Table 2. Baseline patient demographics and clinical characteristics
Variable Dose-escalation cohorts Dose-expansion cohort
Mogamulizumab
+ durvalumab
(n = 21)
Mogamulizumab
+ tremelimumab
(n = 19)
Mogamulizumab
+ durvalumab
(n = 12)
Mogamulizumab
+ tremelimumab
(n = 12)
Age (years), median
(range)
63.0 (23–80) 57.0 (33–76) 68.0 (29–76) 64.5 (46–80)
≥65 years, n (%) 8 (38.1) 4 (21.1) 9 (75.0) 6 (50.0)
Gender, n (%)
Male 10 (47.6) 11 (57.9) 6 (50.0) 7 (58.3)
Female 11 (52.4) 8 (42.1) 6 (50.0) 5 (41.7)
Race, n (%)
White 19 (90.5) 12 (63.2) 12 (100.0) 9 (75.0)
Asian 0 3 (15.8) 0 1 (8.3)
Black or African
American
2 (9.5) 2 (10.5) 0 1 (8.3)
Not reported 0 2 (10.5) 0 1 (8.3)
ECOG performance status,
n (%)
0 7 (33.3) 9 (47.4) 5 (41.7) 3 (25.0)
1 14 (66.7) 10 (52.6) 7 (58.3) 9 (75.0)
Time from diagnosis
(months), median (range)
43.9 (8.2–403.3) 42.1 (12.5–230.5) 25.3 (7.9–59.0) 20.5 (8.4–50.6)
Primary tumor type, n (%)
Pancreatic 1 (4.8) 2 (10.5) 12 (100.0)a 12 (100.0)
a
Colorectal 5 (23.8) 5 (26.3) – –
Sarcoma 5 (23.8) 0 – –
Head and neck 1 (4.8) 3 (15.8) – –
Renal cell 1 (4.8) 3 (15.8) – –
Ovarian 2 (9.5) 1 (5.3) – –
Prostate 1 (4.8) 1 (5.3) – –
NSCLC, non-squamous 1 (4.8) 1 (5.3) – –
NSCLC, squamous 1 (4.8) 0 – –
Anal 0 1 (5.3) – –
Breast 1 (4.8) 0 – –
Other 2 (9.5) 2 (10.5) – –
No. of prior cancer
regimens, n (%)
0 1 (4.8) 0 0 0
1 1 (4.8) 3 (15.8) 0 2 (16.7)
2 2 (9.5) 2 (10.5) 3 (25.0) 2 (16.7)
3 5 (23.8) 2 (10.5) 2 (16.7) 4 (33.3)
4 6 (28.6) 2 (10.5) 3 (25.0) 4 (33.3)
≥5 6 (28.6) 10 (52.6) 4 (33.3) 0
aOnly patients with pancreatic cancer enrolled in dose-expansion cohort. ECOG, Eastern Cooperative Oncology
Group; NSCLC, non-small cell lung cancer.
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38
Table 3. Treatment-related adverse events reported in ≥3 patients or Grade ≥3 in
the same dose cohorts (dose escalation + cohort expansion) for each combination
treatment.
Adverse event No. of patients (%)
Mogamulizumab 1 mg/kg +
durvalumab 10 mg/kg
(n = 19)
Mogamulizumab 1 mg/kg +
tremelimumab 10 mg/kg
(n = 19)
Any Grade Grade ≥3 Any Grade Grade ≥3
Rash maculopapular 7 (36.8) 4 (21.1) 5 (26.3) 2 (10.5)
Fatigue 6 (31.6) 1 (5.3) 3 (15.8) 0
Pruritis 5 (26.3) 0 3 (15.8) 1 (5.5)
Infusion-related reactions 4 (21.1) 0 7 (36.8) 0
Diarrhea 4 (21.1) 0 4 (21.1) 0
Hypothyroidism 3 (15.8) 0 0 0
Stomatitis 1 (5.3) 1 (5.3) 4 (21.1) 0
Rash 1 (5.3) 0 3 (15.8) 1 (5.3)
Colitis 1 (5.3) 1 (5.3) 3 (15.8) 1 (5.3)
Decreased lymphocytes 1 (5.3) 0 1 (5.3) 1 (5.3)
Transaminases increased 1 (5.3) 0 1 (5.3) 1 (5.3)
Autoimmune hepatitis 1 (5.3) 0 1 (5.3) 1 (5.3)
Gastritis 1 (5.3) 1 (5.3) 0 0
Blood CPK increased 1 (5.3) 1 (5.3) 0 0
Hyperglycemia 1 (5.3) 1 (5.3) 0 0
Vomiting 0 0 1 (5.3) 1 (5.3)
Abnormal liver function test 0 0 1 (5.3) 1 (5.3)
Hypertension 0 0 1 (5.3) 1 (5.3)
CPK, creatine phosphokinase.
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39
Table 4. Efficacy results in the dose-escalation and dose-expansion cohorts
receiving the same dose combined.
Mogamulizumab 1 mg/kg +
durvalumab 10 mg/kg
(n = 19)
Mogamulizumab 1 mg/kg +
tremelimumab 10 mg/kg
(n = 19)
ORR, n (%) [95% CI] 1 (5.3) [0.1, 26.0] 1 (5.3) [0.1, 26.0]
CR, n (%) 0 0
PR, n (%) 1a (5.3) 1
b (5.3)
SD, n (%) 5 (26.3) 7 (36.8)
PD, n (%) 12 (63.2) 9 (47.4)
NE, n (%) 1 (5.3) 2 (10.5)
Median OS, months (95% CI) 8.9 (4.3, 18.4) 4.4 (2.5, 13.4)
Median PFS, months (95% CI) 1.9 (1.7, 4.4) 1.9 (1.4, 3.7)
aDuration of response was 10.6 months and time to response was 3.68 months in a patient with
alveolar soft part sarcoma. bDuration of response was 3.7 months and time to response was 1.84 months in a patient with
prostate cancer. CI, confidence interval; CR, complete response; NE, not evaluable; PD, progressive disease; PFS, progression-free survival; PR, partial response; OS, overall survival; SD, stable disease.
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40
Figure Legends
Figure 1. (A) Relationship between clinical response and baseline expression of
CCR4 by various T-cell subsets in peripheral blood. Box and whisker plots (median
and interquartile ranges) are shown. T-cell subsets were defined by flow cytometry
as follows: naive Treg (regulatory T cell) = CD4+CD45RA+FoxP3lo; eTreg (effector
Treg) = CD4+CD45RA–FoxP3hi; and non-supp Treg (non-suppressor) Treg =
CD4+CD45RA–FoxP3lo. (B-D) Changes in peripheral blood eTregs and other CCR4+
T-cell populations in response to therapy. Mean ( standard deviation) change from
baseline in (B) CCR4+ effector regulatory T cells (eTregs), (C) CCR4+ CD4 T cells,
and (D) CCR4+ CD8 T cells. X-axis delineates treatment Cycle (C) and Day (D). See
Table 1 for patient numbers involved. D, durvalumab; M, mogamulizumab; PD,
progressive disease; PR, partial response; SD, stable disease; T, tremelimumab.
Figure 2. Mean percent change from baseline of cell populations in individual
patient tumor biopsies. (A) Mogamulizumab + Durvalumab; BR*=0.3M/3D;
BR**=M/10D; BR***=3M/10D. (B) Mogamulizumab + Tremelimumab; BR**=1M/10T;
BR***=3M/10T. All biopsies were performed during Cycle 2, at the same time as
scans. BR, best response; M, mogamulizumab; PD, progressive disease; PR, partial
response; SCLC, small cell lung cancer; SD, stable disease; T, tremelimumab.
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Published OnlineFirst June 25, 2020.Clin Cancer Res Dmitriy Zamarin, Omid Hamid, Asha Nayak-Kapoor, et al. Phase I StudyTremelimumab in Patients with Advanced Solid Tumors: a Mogamulizumab in Combination with Durvalumab or
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