mogamulizumab in combination with durvalumab or ... · 6/25/2020 · 1 mogamulizumab in...

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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]

Cancer Research. on September 16, 2020. © 2020 American Association forclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on June 25, 2020; DOI: 10.1158/1078-0432.CCR-20-0328

http://clincancerres.aacrjournals.org/

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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




21

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.




22

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




23

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.




24

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




25

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




26

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.




27

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.




28

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




29

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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




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.




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)


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.




39

Table 4. Efficacy results in the dose-escalation and dose-expansion cohorts

receiving the same dose combined.


durvalumab 10 mg/kg

(n = 19)


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.




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.




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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