Phase I Study of P-cadherin targeted Radioimmunotherapy ......CLINICAL CANCER RESEARCH | CLINICALTRIALS: TARGETED THERAPY Phase I Study of P-cadherin–targetedRadioimmunotherapy with

CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY

Phase I Study of P-cadherin–targetedRadioimmunotherapy with 90Y-FF-21101 MonoclonalAntibody in Solid Tumors A C

Vivek Subbiah1, William Erwin2, Osama Mawlawi2, Asa McCoy2, David Wages3, Catherine Wheeler3,Carlos Gonzalez-Lepera4, Holly Liu1, Homer Macapinlac4, Funda Meric-Bernstam1, David S. Hong1,Shubham Pant1, Dao Le4, Elmer Santos4, Jose Gonzalez2, Jason Roszik5, Takeaki Suzuki3,Ruth Ann Subach3, Timothy Madden3, Mary Johansen3, Fumiko Nomura6, Hirokazu Satoh6,Tadashi Matsuura6, Masamichi Kajita7, Eri Nakamura7, Yuichi Funase7, Satoshi Matsushima7, andGregory Ravizzini4

ABSTRACT◥

Purpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimericmAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associ-ated with cancer invasion and metastatic dissemination in manycancer types.We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors.

Patients and Methods: The safety and efficacy of 90Y-FF-21101were evaluated in a phase I 3þ3 dose-escalation study in patientswith advanced solid tumors (n ¼ 15) over a dose range of5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed1 week prior to assess radiation doses to critical organs. Patientswho demonstrated clinical benefit received repeated 90Y-FF-21101administration every 4 months.

Results: 111In-FF-21101 uptake was observed primarily in thespleen, kidneys, testes, lungs, and liver, with tumor uptake observed

in themajority of patients. Organ dose estimates for all patients werebelow applicable limits. P-cadherin expression H-scores rangedfrom 0 to 242with 40% of samples exhibiting scores ≥100. FF-21101protein pharmacokinetics were linear with increasing antibodydose, and the mean half-life was 69.7 (�12.1) hours. Radioactivityclearance paralleled antibody clearance. A complete clinicalresponse was observed in a patient with clear cell ovarian carcino-ma, correlating with a high tumor P-cadherin expression. Stabledisease was observed in a variety of other tumor types, without dose-limiting toxicity.

Conclusions: The favorable safety profile and initial antitumoractivity observed for 90Y-FF-21101 warrant further evaluation ofthis radioimmunotherapeutic (RIT) approach and provide initialclinical data supporting P-cadherin as a potential target for cancertreatment.

IntroductionCadherins are cell-surface glycoproteins that mediate calcium-

dependent cell–cell adhesion required for the formation of solidtissue (1). The so-called classic cadherins, epithelial (E), neural (N),and placental (P)-cadherin, were among the earliest studied and areknown to be associated with adherens junctions of cells. Their struc-tures are notable for having repeated 110 amino acid sequences,

forming extracellular cadherin (EC) domains. These EC domainsprovide the means for cadherins to bind to and interact with othercells and extracellular matrix proteins. Five EC domains have beenidentified, EC1–EC5, with EC1 playing a critical role in mediatedcell–cell adhesion.

Because cadherins have been shown to be overexpressed in a varietyof tumors, they are believed to play a role in effecting malignant cellbehavior (2) and, accordingly, may be an attractive target for tumor-specific therapies. Results fromnumerous preclinical models have nowshown that targeting or disrupting cadherins results in antitumoractivity (2–5). P-cadherin, encoded by the gene CDH3, represents aparticularly attractive target because it is overexpressed in a variety oftumors, with minimal expression in normal tissues of adult humans(Supplementary Fig. S1; refs. 2, 4, 6–9). Park and colleagues and Zhangand colleagues previously characterized an unmodified, humanizedmAb, PF-03732010, directed against P-cadherin (5, 10), which showedpromising antitumor activity in preclinicalmodels. However, althoughPF-03732010 was well tolerated in initial human trials, it did notdemonstrate clinical efficacy (9, 11), suggesting that the unmodifiedanti–P-cadherin antibody may not be suitable for the treatment ofsolid tumors.

More recently, targeted antibodies or peptides have been conjugatedwith radionuclides to enhance their antitumor activity. This approachhas been used successfully to treat well-differentiated neuroendocrinetumors of the pancreas (12, 13), prostate cancer (14), and lympho-mas (15). In this paper, we describe the initial Phase 1 study results for achimeric human/mouse immunoglobulin G (IgG1) monoclonal

1Department of Investigational Cancer Therapeutics, Division of Cancer Medi-cine, The University of Texas MD Anderson Cancer Center, Houston, Texas.2Department of Imaging Physics, Division of Diagnostic Imaging, The Universityof Texas MD Anderson Cancer Center, Houston, Texas. 3FUJIFILM Pharmaceu-ticals U.S.A., Inc., Cambridge, Massachusetts. 4Department of Nuclear Medicine,Division of Diagnostic Imaging, The University of Texas MD Anderson CancerCenter, Houston, Texas. 5Department of Melanoma Medical Oncology, Divisionof Cancer Medicine, The University of Texas MD Anderson Cancer Center,Houston, Texas. 6Perseus Proteomics, Inc., Tokyo, Japan. 7FUJIFILM ToyamaChemical Co., Ltd., Chiba, Japan.

Note: Supplementary data for this article are available at Clinical CancerResearch Online (http://clincancerres.aacrjournals.org/).

Corresponding Author: Vivek Subbiah, The University of Texas MD AndersonCancer Center, 1515 Holcombe Blvd – Unit 455, Houston, TX 77030. Phone: 713-563-1930, Fax: 713-792-0334; E-mail: [email protected]

Clin Cancer Res 2020;26:5830–42

doi: 10.1158/1078-0432.CCR-20-0037

�2020 American Association for Cancer Research.

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antibody directed against P-cadherin, conjugated to Yttrium-90 (90Y)for the treatment of solid tumors (90Y-FF-21101). Because 90Y emitsbeta particles with an average penetration of 4 mm in soft tissue, thebeta ray from a 90Y-labeled antibody renders DNA damage tothe bound cells and also to the adjacent or more distant cells dueto its longer range compared with other beta emitters (16). Ourpreclinical research has shown preferential uptake of 90Y-FF-21101in P-cadherin–expressing tumors, and antitumor activity in mousexenograft models of ovarian and lung adenocarcinoma (Supple-mentary Figs. S1–S3; ref. 17, 18). On the basis of these results, thefirst-in-human phase I trial of 90Y-FF-21101 was conducted to evalu-ate the dosimetry, safety and tolerability, pharmacokinetics, andantitumor activity in patients with advanced solid tumors.

Patients and MethodsTrial design and patient eligibility

The phase I, first-in-human, open-label, dose-escalation study wasconducted at the University of Texas MD Anderson Cancer Center(MDACC, Houston, TX), in accordance with the Declarations ofHelsinki. The primary objective was to determine the safety andtolerability in patients who receive 90Y-FF-21101 for the treatmentof advanced solid tumors refractory to or relapsed from prior therapy(ClinicalTrials.gov Identifier: NCT02454010). Secondary endpointsincluded determination of overall response rate (ORR), duration ofresponse, progression-free survival (PFS), overall survival (OS), andevaluation of serum antibody protein pharmacokinetics (PK) andpresence of human anti-CDH3 human/mouse chimeric antibody(HACA). Baseline tumor P-cadherin expression was evaluated in allpatients with a biopsy-accessible tumor to characterize and correlateresponse to potential markers of activity. To allow patients to proceedto treatment with 90Y-FF-21101, estimation of the radiation absorbed90Y-FF-21101 dose to marrow and major organs was evaluated bymeasurement of Indium-111 (111In)-FF-21101 biodistribution, and, asa secondary objective, selective uptake of 111In-FF-21101 in tumortissue was also assessed.

The protocol was approved by the institutional review board atMDACC, and all patients provided written informed consent prior to

all study-related procedures. Adult patients must have been ≥18 yearsof age with histologically or cytologically confirmed advanced solidtumor malignancy and refractory or relapsed from prior therapy withno available therapy likely to provide clinical benefit or for whom noalternative therapy is available. Patients had to be at least 3 weeksbeyond the last chemotherapy (or ≥5 half-lives, whichever wasshorter), radiotherapy, major surgery, or experimental treatment andrecovered from all acute toxicities (≤ grade 1). Adequate performancestatus [Eastern Cooperative Oncology Group (ECOG) ≤ 2], hemato-logic parameters, renal and hepatic function, and at least one mea-surable disease site that meets target lesion requirements by ResponseEvaluation Criteria in Solid Tumors (RECIST) v1.1, were required.

Dose escalation proceeded in a standard 3þ3 design with obser-vation for dose-limiting toxicity (DLT) for 6 weeks post the initialtreatment. A minimum of 6 weeks elapsed between the last subjectdosed in a cohort and the first subject in a new cohort. The highest90Y-FF-21101 level below the level eliciting DLTwould be declared themaximum tolerated radioactivity. The dose-escalation phase wasfollowed by an expansion phase, which is currently ongoing.

Radiolabeled antibody preparationRadiolabeling of FF-21101 with 111InCl3 for dosimetry or with

90YCl3 for treatment was carried out by the clinical site radio-pharmacy. The mAb conjugated to DOTA (FF-21101) was providedas a 5 mg/mL solution in 250 mmol/L sodium acetate, pH 5.5, byFUJIFILM Diosynth Biotechnologies U.S.A., Inc. A clinical formula-tion buffer [25 mmol/L sodium acetate, 2 mg/mL ascorbic acid,0.3 mg/mL diethylenetriaminepentaacetic acid (DTPA), and 0.72%sodium chloride, pH 5.5] was provided for dilution. 111In chloridesterile solution (Mallinckrodt, Inc.) and 90Y chloride sterile solution(Eckert & Ziegler Radiopharma, GmbH) were used for radiolabeling.Solutions were prepared to maintain a specific radioactivity of 1 mCi/mg (�10%) 111In-FF-21101 for dosimetry and 8 mCi/mg (�10%) for90Y-FF-21101 at the time of injection. Validation procedures wereperformed at each site prior to patient dose preparation. Threeconsecutive batches of 40mCi 90Y-FF-21101 were prepared and testedagainst acceptance criteria for appearance, radioactivity, radiochem-ical purity, pH, bacterial endotoxin, sterility, and stability. Qualitycontrol testing of each patient dose was also performed prior toadministration including visual inspection (clear, colorless to paleyellow, free of visible particular matter) and radiochemical purity byinstant thin-layer chromatography (≥95%). Other quality attributesof prepared drug doses (purity by SEC, immunoreactivity by ELISA)were optionally tested and documented in site-specific compoundingvalidation records.

111In-FF-21101 dosimetry111In radioactivity in serum and urine was evaluated, and axial

SPECT, CT, and fused (SPECT/CT) and whole-body anterior/posterior planar 111In scintigraphy was performed in all patientsapproximately 1 week prior to administration of the therapeutic doseto assess the acceptability of radiation dose estimates to critical organsand red marrow. The prepared 111In-FF-21101 dose was administeredintravenously through a 0.22-mm in-line filter by slow injection at arate not to exceed 1 mL/minute (approximately 10 minutes). Anteriorand posterior whole-body planar scintigrams were acquired using adual-head gamma camera (Symbia S, SiemensMedical Solutions USA,Inc.) at 0.25, 4, 24, 72, and 144 hours after 111In-FF-21101 adminis-tration; SPECT images were acquired 24 hours postadministration,followed by aCT scan (750HD,GEHealthcare) for SPECT attenuationcorrection and organ volume contouring. The images were used to

Translational Relevance

Cadherins are cell-surface glycoproteins that mediate calcium-dependent cell–cell adhesion required for the formation of solidtissue. Several cadherins, including placental (P)-cadherin, areoverexpressed in many tumor types, correlating with increasedtumor cell motility and invasiveness. P-cadherin is of particularinterest clinically because, while highly expressed in many tumortypes, it is minimally expressed in normal tissue, making it aselective antitumor target. Promising activity has been demon-strated in preclinicalmodels usingmonoclonal antibodies targetingP-cadherin. Here, we report the clinical activity of 90Y-FF-21101,an anti–P-cadherin antibody conjugated to a radionuclide toenhance its antitumor activity. In this first-in-human phase I study,90Y-FF-21101 was well tolerated and demonstrated signs of anti-tumor activity in patients with advanced solid tumors, including acomplete response in a patient with ovarian cancer. These resultsprovide initial clinical data supporting the potential for P-cadherinas a target for cancer treatment using a radioimmunotherapeuticapproach.

Phase I Study of 90Y-FF-21101 in Solid Tumors

AACRJournals.org Clin Cancer Res; 26(22) November 15, 2020 5831




generate organ region of interest time–activity curves (TAC), whichwere fitted to exponential functions using Prism 6 (GraphPad) toobtain 111In-FF-21101 and, by converting from 111In to 90Y radioactivedecay, estimated 90Y-FF-21101 organ residence times. Blood sampleswere obtained at 0.5, 1, 2, 4, 24, 72, and 144 hours after 111In-FF-21101administration to compute 111In-FF-21101 and 90Y-FF-21101 redmarrow TACs and residence times using the Sgouros formula (19).Residence times and CT-based lung, liver, kidney, and spleen organmass estimates were entered into OLINDA/EXM 1.1 (VanderbiltUniversity, Nashville, TN) to generate estimated 111In-FF-21101 and90Y-FF-21101 organ doses (20). Serum and urine 111In radioactivityconcentrations (% ID/L) were measured using a precalibrated gammascintillation counter.

90Y-FF-21101 treatmentThe administered radioactivity in the first cohort was 5 mCi/m2

(185 MBq/m2; �10%) 90Y-FF-21101, which was then escalated in5 mCi/m2 increments to 10, 15, 20, and 25mCi/m2 (370, 555, 740, and925 MBq/m2; �10%) in subsequent cohorts. 90Y-FF-21101 wasadministered intravenously through a 0.22-mm in-line filter on day1 by slow injection at a rate not to exceed 1mL/minute (approximately10 minutes). Patients were monitored for 4 hours after each dose of90Y-FF 21101 for infusion reactions. At the highest dose level to beexplored (25 mCi/m2), the maximum radioactivity allowed per infu-sionwas limited to 60mCi (2,220MBq) as a safety precaution based ondosimetry performed in animals and estimated radiation absorbeddose to the lungs that would exceed the maximum allowable limitdefined for external beam radiotherapy (21, 22). The delivered activityestimates were required to be below standard limits for external beamradiotherapy typically used for nonmyeloablative radioimmunother-apeutic (RIT; <3 Gy for red marrow, <30 Gy for liver, and <20 Gy forkidney and lung). If an estimate exceeded the limit, option fortreatment at a lower radioactivity was allowed if within allowablelimits.

For purposes of scheduling study procedures, cycles were defined aseach 28-day period following the initial 90Y-FF-21101 administration.On the basis of estimates of organ radiation dose being well below thestandard limits for external beam radiation, the lack of observedtoxicities, coupled with response observed including an objectiveresponse observed at Cohort 3, the protocol was amended to allowrepeated administration at a frequency of every 4 months in respond-ing patients or patients who demonstrated clinical benefit if thefollowing criteria were fulfilled: hemoglobin ≥10 g/dL, absolute neu-trophil count ≥1.5 � 109 cells/L, platelets >100,000 � 106 cells/L,creatinine≤1.5� upper limit of normal (ULN), or creatinine clearance≥60 mL/minute� 1.73 m2/BSA, bilirubin <1.5�ULN, ALT and AST≤2.5� ULN (<5� ULN if liver metastases), and ECOG Performancestatus ≤2. Additional therapeutic doses of 90Y-FF-21101 were alloweduntil disease progression (PD), observation of unacceptable adverseevents (AE), intercurrent illness, or changes in the patient's conditionthat prevented further study participation.

Efficacy assessmentDisease assessments based on CT or MRI were obtained at week 8

and every 8 weeks thereafter until documented PD and classifiedaccording to RECIST v1.1 (23). The primary efficacy endpoint was theproportion of subjects with objective response [complete response(CR) þ partial response (PR)] achieved by week 8 (ORR). The bestoverall response was defined as the best response recorded across alltime points. Clinical benefit was defined as confirmedCR, PR, or stabledisease (SD). When SD was believed to be the best response, it must

also have met the protocol-specifiedminimum duration from baseline(8 weeks), including for assessment of clinical benefit. Progression-freesurvival was calculated from the date of first dose of 90Y-FF-21101 tothe date of first objective evidence of disease progression or death,whichever was earlier. Overall survival was calculated from the date offirst dose of 90Y-FF-21101 to the date of death due to any cause.

Safety assessmentsSafety and tolerability based onAEs and laboratory parameters were

assessed from the day of 111In-FF-21101 administration through theend of study (28 days after the last treatment). Adverse events wereclassified according to the Medical Dictionary for Regulatory Affairs(MedDRA) and graded using NCI Common Terminology Criteriafor Adverse Events (CTCAE) version 5.0. Patients were monitoredduring the conduct of the physical examination throughout the studyfor signs of potential pulmonary toxicity (e.g., cough, wheezing,dyspnea with orwithout fever, radiation pneumonitis, etc.). Radiologicassessment could be used as necessary to confirm findings, andsymptoms treated with corticosteroids as required. Eye examinationsconsisted of visual acuity and field tests, slit lamp examination fundo-scopy, and optical coherence tomography performed at cycle 1 andevery 30 days thereafter. Dose modification or delay was allowed onthe basis of protocol-defined criteria.

DLT was defined as grade 4 hematologic toxicity lasting ≥ 7 days;grade 4 neutropenia with a fever (single temperature > 38.3�C orsustained temperature of ≥ 38�C for more than 1 hour); ≥ grade 3thrombocytopenia with clinically significant bleeding; failure of plate-lets, ANC, or hemoglobin to recover to ≤grade 1 within 12 weeks ofdosing with 90Y-FF-21101, despite allowance of supportive measuresto aid recovery (e.g., RBC, platelet transfusions, growth factors); grade4 nonhematologic toxicity of any duration; grade 3 nonhematologictoxicity lasting ≥ 3 days, despite the use of supportive care measures(e.g., antiemetics, antidiarrheals); or any protocol defined ophthal-mologic finding. Aminimum of 6 weeks would elapse between the lastsubject dosed in a cohort and the first subject in a new cohort for safetyassessment. The highest 90Y-FF-21101 dose level below the dose leveleliciting DLT, or the highest dose tested in the absence of DLT, wasdeclared the maximum tolerated activity.

Patients remained on study until they chose to discontinue partic-ipation or developed PD, unacceptable AEs, or an intercurrent illnessor change in medical status that prevented further study participation.Long-term follow-up involved a clinic visit or telephone call every3 months for up to 12 months.

Pharmacokinetic assessmentSerum FF-21101 antibody concentrations were assessed during

cycle 1 by electrochemiluminescence (ECL) analysis using a validatedmethod with a dynamic range of 5–1,000 ng/mL. Data were collectedusing a MSD Sector Imager 6000 and pharmacokinetic parametersestimated using a noncompartmental approach (Phoenix pharmaco-kinetic software, Certara). Pharmacokinetic parameters (trough levels,t1/2, Tmax, Cmax, AUC, CL) were assessed on the basis of individual andmean serum concentrations of FF-21101 on days 1, 8, and 15. Analysisof anti-drug antibodies (ADA) was performed in samples obtainedon days 1 (pretreatment), 8, 15, and 22 of all cycles using a bivalentECL immunoassay fully validated in human serum that bindsanti–FF-21101 to both biotin- and ruthenium-labeled FF-21101.Qualitative ECL immunoassay was used to initially screen for thepresence of antibodies to FF-21101. Test samples that confirmedpositive for the presence of anti–FF-21101 antibodies were titratedto report the sample titer.

Subbiah et al.

Clin Cancer Res; 26(22) November 15, 2020 CLINICAL CANCER RESEARCH5832




Analysis of P-cadherin expressionP-cadherin expression by IHC in formalin-fixed paraffin-embedded

archived or fresh tumor biopsy was correlated with clinical outcome asan exploratory endpoint. IHC staining of paraffin-embedded 4-mmpatient tumor tissue sections was performed using a Benchmark Ultraautomated immunostaining device (Ventana Medical Systems) withheat-induced antigen retrieval and Optiview DAB detection. Murinemonoclonal anti–P-cadherin antibody was purchased from BD Bio-sciences (material number 610227/8) and applied at 2 mg/mL. Poly-mer-negative control serum (BioCare Medical) was used as a negativecontrol. Samples were processed at a single CLIA reference laboratory(Covance). P-cadherin expression was scored on the basis of stainingintensity and the percentage of positive tumor cells with membranestaining. Staining intensity was rated as 0, absent; 1, weak; 2, moderate;or 3, strong. The approximate percentage of tumor cells with mem-brane staining at each intensity was reported from 0% to 100%. AnH-score for each tissue specimen was calculated as follows, based onthe percentage of cells at each intensity: H-score¼ 3� (% of cells at 3þintensity) þ 2 � (% cells at 2þ intensity) þ 1 � (% cells at 1þintensity). The maximum H-score was 300, representing 100% oftumor cells positive for P-cadherin with a staining intensity of 3.

Statistical analysesResponse rates were summarized using the number and percentage

of patients with best overall response of CR, PR, or SD. For PFS andOS,the Kaplan–Meier product-limit method was used to estimate themedian survival. Patients who did not experience disease progressionor death were censored at the date of the last evaluable diseaseassessment. For patients who have not died, OS was censored at thedate the patient was last known to be alive or the date of last contact,whichever was later. Descriptive statistics were used to summarizedemographic data, baseline disease characteristics, and safety out-comes in the dose-escalation phase. All analyses were performed usingSAS for Windows version 9.3 or higher (SAS Institute, Cary, NC).

ResultsPatient characteristics

From January 21, 2016 to July 1, 2019, 15 patients (6 males, 9females) with advanced primary tumors (stage IV) were treated in fivecohorts of the 3þ3 dose-escalation phase study (Table 1). Patientswith a variety of tumor types were enrolled including sarcomas[leiomyosarcoma, liposarcoma, clear cell sarcoma (n ¼ 2), desmo-plastic small round cell tumor], gynecologic cancers [vaginal, ovarian(n ¼ 2)], gastrointestinal cancers (colon, appendix, cholangiocarci-noma), and neuroendocrine tumors (lung, pancreatic). All patientswere heavily pretreated and had received prior surgery, radiation,and/or chemotherapy with a median number of prior treatmentregimens of 6.5 (range 3–10).

DosimetryImages from whole-body scintigraphy and single-photon emission

CT/X-ray CT (SPECT/CT) demonstrated 111In-FF-21101 uptake pri-marily in the spleen, kidneys, testes, lungs, and liver (Table 2). Total90Y Gy organ radiation dose estimates are shown by increasingadministered activity over cohorts 1–5. For all patients, estimates forthe 90Y-FF-21101 administered activity were below the applicablelimits for external beam radiotherapy to red marrow (<3 Gy), liver(<30 Gy), kidneys, and lungs (<20 Gy; ref. 22). The spleen had thehighest amount of uptake in all patients except one who had priorsplenectomy.

Although only limited assessment of tumor localization could beperformed, radiotracer activity was appreciable at the location of theprimary tumor and in known sites ofmetastatic disease in themajorityof patients evaluated. Figure 1A (i–iii) shows axial SPECT, CT, andfused (SPECT/CT) images of the pelvis obtained 24 hours after theadministration of 5 mCi/m2 (5.54 mCi) 111In-FF-21101 in a patientwith squamous cell carcinoma of the anus enrolled in the first cohort,providing early radiographic evidence of P-cadherin targeted antibodyuptake in tumor. Increased radiotracer uptake was shown correspond-ing to a 6.5 � 5.0 � 4.4 cm soft tissue metastasis in the right pelvis inthis patient, with serial whole-body planar images demonstrating thetemporal accumulation of radioactivity in the pelvic lesion and inmetastases to the right hepatic lobe and anterior abdominal wall andrectal regions, with maximal tumor uptake observed by 72 hourspostadministration [Fig. 1A (iv)]. Image (iv) also reveals graduallyincreasing splenic uptake. Although appreciable tumor uptake wasobserved, the patient unfortunately was withdrawn following dosim-etry due to rapidly progressing disease. Overall, evidence of radiotraceractivity in tumor was observed in all but two patients evaluated, onewith ovarian cancer who achieved aCR as further described below, andanother with cholangiocarcinoma for which uptake in the periportalregion was indeterminate. The latter patient had received three treat-ments approximately 4 months apart, with stable disease maintainedthrough cycle 12 (48 weeks) before progressing.

90Y-FF-21101 treatment and P-cadherin stainingSubsequent 90Y-FF-21101 treatment was initiated at an adminis-

tered radioactivity of 5 mCi/m2 (185 MBq/m2; �10%), similar tothat used in previous clinical trials for 90Y-drug conjugates (24–28),at a specific activity of 8 mCi/mg antibody. Dose was escalated to

Table 1. Patient characteristics and demographics.

Dose-escalation phase Treated patients (n¼ 15)

Median age, years (range) 57 (31–70)Male/female, n 6/9Disease, n

Soft tissue sarcoma 5Leiomyosarcoma 1Liposarcoma 1Clear cell sarcoma 2Desmoplastic small round cell tumor 1

Chondrosarcoma 1Gynecologic cancer 3

Vaginal 1Ovarian 2

Gastrointestinal cancer 3Colon 1Appendix 1Cholangiocarcinoma 1

Neuroendocrine tumor 2Lung 1Pancreatic 1

Other (papillary thyroid carcinoma) 1ECOG performance status, n

0 11 14

90Y-FF-21101 dose per single administrationMinimum 7.7 mCi (285 MBq)Maximum 51.6 mCi (1909 MBq)

Median no. of prior treatment regimens (range) 6.5 (3–10)






25 mCi/m2 over five cohorts, with 5 patients who received more thanone treatment (Fig. 2A). The median (range) time on study followingthe first 90Y-FF-21101 administration was 24 (4–90) weeks. Tumorsamples from 13 of 15 subjects were available for IHC analysis. P-cadherin staining was predominantly localized in the tumor cellmembrane, with some nontumor staining of occasional fibroblastsand endothelial cells (Fig. 2B, a–d). P-cadherin expression H-scoresranged from 0 to 242 with 40% of samples exhibiting scores ≥100. Onesubject with metastatic clear cell ovarian carcinoma had the mostmarked P-cadherin staining (H-score of 242, Fig. 2A; Fig. 2B, d) andachieved a clinical CR by RECIST, as further described below. StrongP-cadherin staining was also observed in patients with pancreaticneuroendocrine tumor, intrahepatic cholangiocarcinoma, and sarco-ma, specifically in clear cell, smooth muscle tissue.

Pharmacokinetics and ADA titersOver the dose range administered of 0.625 to 3.2 mg/m2 FF-21101

protein, FF-21101 antibody pharmacokinetics in serum demonstratedgenerally dose proportional increases in exposurewith increasing dose,as measured by maximum concentration (Cmax) and area-under-the-concentration-time curve from zero to infinity (AUC0-¥), with a mean(�StdDev) half-life for the circulating antibody in serum of 69.7(�12.1) hours [Fig. 1B (i)]. With a physical half-life for 90Y of64.1 hours, the effective half-life for 90Y-FF-21101 was calculated as33.4 hours. Mean clearance and steady-state volume of distribution(Vss) for the FF-21101 antibody ranged from 10.2 to 43.7 mL/hour/kgand from 1,390 and 3,940 mL, respectively. On the basis of a limitednumber of patients per cohort, there was high variability in exposurewithin each cohort. However, the serum pharmacokinetics of theFF-21101 protein appears to be linear and not dose dependent inhumans. Mean radioactivity clearance in serum (111In-FF-21101percent injected dose per liter, %ID/L) paralleled antibody clearancefrom 0 to 144 hours [Fig. 1B (ii)], with an initial %ID/L of 20% at0.5 hours (CV, 33%) that was more rapidly eliminated to < 1%measurable at 144 hours postadministration. Evidence of the forma-tion of circulating antibodies against the FF-21101 antibody was ob-served in only 2 patients within 4 weeks following the initial treatment.

In both patients enrolled at Cohort 4 (20 mCi/m2), ADA titers rangedfrom low-intermediate to high and remained stable throughout thecourse of treatment. It is unknown at this time if the ADA isneutralizing. However, these patients went on to receive subsequentdoses of 90Y-FF-21101 andmaintained stable disease, one for 4monthsand one for 12 months.

Clinical activityOne patient achieved a CR; no other patients achieved a PR, so the

ORR was 6.7% (1/15). Median PFS was 24 weeks, and the median OSwas 90 weeks. The clinical benefit rate defined as confirmed CR, PR, orSD for a minimum of 8 weeks was 73% (11/15 patients).

The CR was observed in a 60-year-old woman with metastatic clearcell ovarian carcinoma (Fig. 3). The patient was a nulligravida femalewhopresentedwith a persistent cough for severalmonths. A diagnosticwork-up at the local emergency room for worsening abdominal pain,nausea, and vomiting confirmed a 10-cm left pelvic mass and a 6-mmsplenic lesion suspected to be metastatic disease. Her CA-125 waselevated at 83 U/mL. She underwent exploratory laparotomy, totalabdominal hysterectomy with bilateral salpingo-oophorectomy, rad-ical debulking, left pelvic and para-aortic lymph node sampling, andpartial omentectomy. Final pathology showed a stage IIC clear cellcarcinoma of the ovary. According to the operative report, the spleenwas unremarkable and she was optimally debulked. Comprehensivenext-generation DNA sequencing of the resected tumor (FoundationMedicine) showed PIK3CA E545K and N1044S mutations. Surgerywas followed by six cycles of carboplatin/paclitaxel. Evidence ofprogressive nodal disease was seen on CT scan approximately 1 yearlater. Pelvic and para-aortic lymphadenectomy showed 10 of 13positive lymph nodes and was followed by radiotherapy (56 Gy in27 fractions to high-risk areas) and hepatic resection of metastasisapproximately 7 months before study entry. Further analysis of thepatients’ tumor confirmed the previous PIK3CAmutation [OncologyHotspot Panel (50 genes), sema4], and the following profile: cMET,PD-1, PTEN, TOP2A, and TUBB3-positive, PD-L1–negative (CarisLife Sciences). A follow-up restaging scan showed recurrence in the leftaxilla, and biopsy of the left axillary lymph node at the time of

Table 2. Normalized 90Y-FF-21101 organ radiation–absorbed dose estimates based on 111In-FF-21101 dosimetric imaging.

Mean (Total Gy)

Organ

Mean(mGy/mCi)(n ¼ 15) StdDev

CV(%)

Cohort 15 mCi/m2

(n ¼ 3)

Cohort 210 mCi/m2

(n ¼ 3)

Cohort 315 mCi/m2

(n ¼ 3)

Cohort 420 mCi/m2

(n ¼ 3)

Cohort 525 mCi/m2

(n ¼ 3)

Spleen 1,031.5 399.9 38.8 12.82 18.99 20.38 43.95 37.42Testes 339.5 122.6 36.1 3.22 11.01 N/A 15.62 14.06Kidneys 219.7 75.8 34.5 2.70 3.20 6.62 8.92 8.15Lungs 168.9 56.9 33.7 1.88 2.88 4.51 6.65 8.05Liver 160.6 58.5 36.4 1.85 2.73 4.08 6.39 7.32Heart wall 89.7 18.1 20.1 0.67 1.99 2.43 3.84 5.08Osteogenic cells 34.7 13.2 38.1 0.30 0.71 0.98 1.24 2.30Red marrow 29.6 11.0 37.1 0.30 0.56 0.78 1.02 1.87Total body 25.7 2.6 10.1 0.20 0.55 0.69 0.99 1.38Ovaries 14.6 4.3 29.6 0.11 0.26 0.36 0.61 0.93Uterus 14.6 4.3 29.6 0.11 0.26 0.36 0.61 0.93All other organs 12.5 5.1 40.6 0.09 0.29 0.36 0.50 0.86

Note: All 16 (7 male, 9 female) patients were evaluated (1 male patient did not proceed to therapy). Total dose estimates for each patient were their individualnormalized dose estimates multiplied by their administered 90Y radioactivity, and are shown by increasing administered activity over cohorts 1–5 (testes N/A forCohort 3, as all were female). 111In-FF-21101 uptake was observed primarily in the spleen, testes, kidneys, lungs, and liver. For all patients, estimates for 90Y-FF-21101administered activitywere below the applicable limits for external beam radiotherapy (<3Gy to redmarrow,<30Gy to the liver, and<20Gy to the kidneys and lungs).

Subbiah et al.





Figure 1.

Dosimetry andpharmacokinetics in a phase I study of 90Y-FF-21101.A,Dosimetric imaging in a 33-year-oldmalewithmetastatic squamous cell carcinomaof the anus.Axial SPECT (i), CT (ii), and fused (SPECT/CT) images (iii) of the pelvis obtained 24 hours after the administration of 5.54mCi of 111In-FF-21101 demonstrate increasedradiotracer uptake corresponding to a 6.5� 5.0�4.4 cmsoft tissuemetastasis in the right pelvis (white arrows). Serialwhole-bodyplanar images in the anterior viewdemonstrate the time course of 111In-FF-21101 uptake in this patient (iv). Thepatient hadmetastases to the right anterior abdominalwall, right pelvis, and rectal region,with maximal tumor uptake observed by 72 hours postadministration (green arrow heads). Red arrows depict sequential radiotracer uptake in the right pelvicmetastasis shown on the axial images. In addition, there was heterogeneous radiotracer activity at the site of multifocal metastases in the right hepatic lobe, thelargest with central necrosis [circled in whole body planar (iv) and SPECT/CT (v) images]. Gradually increasing uptake was also noted in the spleen. B, Mean(�StdDev) serumFF-21101 antibodyprotein concentration versus time following a single dose of 90Y-FF-21101 (n¼ 3/cohort except Cohort 1wheren¼ 1; i). Followingthe administration of 5 to 25 mCi/m2 90Y-FF-21101 over Cohorts 1–5 (equal to 0.625 to 3.2 mg/m2 FF-21101 protein), antibody protein was measurable in serum up to300 hours postadministration. High variability in exposure was observedwithin each cohort; however, the serumpharmacokinetics of the FF-21101 protein appearedto be linear and not dose dependent in humans. Themean (�StdDev) biologic half-life for the circulating antibody in serumwas 69.7 (�12.1) hours, with an effectivehalf-life for 90Y-labeled FF-21101 of 33.4 hours. Radioactivity clearance in serum (111In-FF-21101 percent injected dose per liter, %ID/L) is shown for all patients inthe dosimetry phase (n¼ 16) following administration of 5mCi (�10%) 111In-FF-21101, containing 5mgFF-21101, approximately 1week prior to 90Y-FF-21101 dosing (ii).Radioactivity clearance paralleled antibody clearance from0 to 144 hours. Themean initial %ID/Lwas 20%at 0.5 hours (CV, 33%; see inset) and < 1% at 144 hours post111In-FF-21101 administration.






evaluation for study entry was positive formetastatic clear cell carcino-ma. In addition, mildly enlarged abdominal adenopathy was observedin the para-aortic region in addition to numerous enlarged nodes in theretroperitoneum surrounding the abdominal aorta and a prominentgastro-hepatic node. The patient was then referred for study enroll-ment in the third dose-escalation cohort to receive treatment with 90Y-FF-21101 at a dose of 15 mCi/m2 (24.2 mCi). Visible tumor uptake in

the target axillary nodes was not clearly appreciable in serial whole-body planar scintigrams nor the SPECT image acquired at 24 hoursfollowing 111In-FF-21101 administration. However, following a single90Y-FF-21101 treatment, a PR in target lesions was observed at theinitial restaging at cycle 2 (week 8), which was confirmed at week 16(59.9% decrease in sum of diameters of target lesions). Given theexcellent response, the protocol was amended to allow administration

Figure 2.

P-cadherin staining and response totherapy in a phase I dose-escalationstudy of 90Y-FF-21101. A, Best responseto therapy in the phase I dose-escalationstudy by P-cadherin expression H-scoreand 90Y-FF-21101 dose. Dose administra-tion is shown by circles. NE, not evalu-able. B, Representative IHC images ofP-cadherin staining in human tumorsamples showing: a, weak staining ofcholangiocarcinoma (H¼ 108) withmin-imal background; b, moderate stainingof ovarian carcinoma (H ¼ 180); c, focalstrongmembranous staining of clear cellsarcoma (H ¼ 115); and d, strong mem-branous and cytoplasmic staining ofovarian carcinoma (H¼ 242) in a subjectwith a RECIST complete response. C,Percent change from baseline in tumorburden for all patients enrolled inthe phase I dose-escalation study of90Y-FF-21101 by P-cadherin expressionH-score.

Subbiah et al.





of additional doses in responding patients and her treatment wascontinued every 4 months for three additional doses with continueddisease response (Fig. 3B), followed by an additional fifth doseapproximately 7 months later (cycle 20). Restaging at cycle 24 sub-sequently showed achievement of a CR of her target lesion (axillarylymph node), and no evidence of metastatic abdominopelvic disease.The patient was thereafter followed by her local physician every othercycle beginning with cycle 25 and hasmaintained a CR with no furthertreatment. CA-125 values decreased from 30 to 15 U/mL over thecourse of 90Y-FF-21101 treatment and, as noted above, tumor responsein this patient correlated with a high P-cadherin expression H-score >200 (242), the highest documented on study (Fig. 2A–C).

An additional patient with metastatic low-grade serous ovariancarcinoma had stable disease following a single 90Y-FF-21101 treat-ment at a dose of 10 mCi/m2 (21.9 mCi). This patient had disease

involving the rectum and abdominal wall and was progressing prior tostudy entry in the 2nd cohort, with a P-cadherin expression H-score of180. Although disease was stable following 90Y-FF-21101 treatment,the patient subsequently came off study after 16 weeks due to personallogistical (nonmedical) reasons. Stable disease responses were main-tained for approximately 50 weeks on study in an additional 4 patients,one with a pancreatic neuroendocrine tumor (NET) treated with asingle dose at the lowest dose level of 5 mCi/m2 (9.8 mCi), one withmetastatic intrahepatic cholangiocarcinoma treated in the third cohortwith 15 mCi/m2 (25.4 mCi) for 3 doses, one with a lung NET treatedwith 2 doses of 20 mCi/m2 (36.3 mCi) administered 4 months apart,and one with a clear cell sarcoma who received a total of 4 dosesadministered 4 months apart at the highest dose level of 25 mCi/m2

(49.5 mCi; Fig. 2A). P-cadherin expression H-scores were ≥ 100 intwo of these patients (clear cell sarcoma and pancreatic NET), but

Figure 3.

Complete response achieved with 90Y-FF-21101 treatment in a patient with metastatic clear cell ovarian carcinoma.A, Therapy timeline of a 60-year-old female withmetastatic clear cell ovarian carcinoma and response to 90Y-FF-21101 therapy based on tumor marker (CA-125, U/mL) and target lesion size (longest diameter, mm).B, Serial CT images after 90Y-FF-21101 treatment showing left axillary adenopathy; target node reduced from 1.6 cm in the longest diameter at screening to0.6� 0.6 cm (red circle and arrows) following administration of four 15 mCi/m2 (24.2 mCi) 90Y-FF-21101 treatments administered 4months apart; an additional fifthdose was administered approximately 7 months later. A complete response was achieved by cycle 24 and has been maintained over 1 year to date without furtherneed for therapy.






notably absent in the patient with lung NET (H-score of 3). Patientswith an H-score ≥ 100 remained on study for a median (range) of54 (47–64) weeks compared with 8 (4–46) weeks in patients with anH-score < 100.

Safety and treatment-related adverse eventsDLT was not observed in any patient on study and dose reductions

were not required over the course of the dose escalation. Patients didnot exceed the allowed per treatment amount of calculated radiationexposure (Table 2). Treatment-emergent AEs (all events related andunrelated) were typical of a phase I solid tumor trial, with the mostcommon being lymphopenia (75%), increased AST (56%), fatigue(56%), anemia (44%), diarrhea (44%), dysgeusia (38%), leukopenia(38%), increased ALT (25%), anorexia (25%), constipation (25%),dizziness (25%), dyspnea (25%), and hyperkalemia (25%).

Similar to other 90Y-conjugated therapeutic antibodies, there werereversible myeloid effects (28, 29). Themost common drug-related AEwas lymphopenia, which occurred in 11 (68.8%) of 16 patients [grade 3(n¼ 3) or 4 (n¼ 1) severity in four patients, 25%;Table 3]. In cohort 4,one subject experienced grade 4 lymphopenia within 1 week of thetherapeutic dose but had normal overall white blood cell counts; thisevent did not meet DLT criteria. Transient grade 3 lymphopenia andleukopenia was observed in one additional patient at cohort 4. Therewere no SAEs reported at Cohort 4, and no grade 3 or 4 lymphopeniaobserved in cohort 5 (25 mCi/m2). Drug-related leukopenia andthrombocytopenia occurred in 31.3% and 25.0% of patients, respec-tively, and were of grade 3 or 4 severity in only one patient each. Grade1 or 2 dysgeusia, increased AST, and rash were other common drug-related AEs observed in more than 10% of patients. All AEs werereversible. No evidence of pulmonary function impairment or oculareffects was observed. There were no grade 3 or 4 AEs observed at thehighest dose level (25 mCi/m2), and no drug-related serious AEs,discontinuations, or deaths were observed on study. A maximumtolerated administered activity was therefore not reached in doseescalation based on the lack of DLT in patients receiving up to60 mCi/dose and cumulative doses up to 100 mCi administered onan every 4-month schedule.

DiscussionAntigens that are unique or virtually unique to tumors offer the

promise of targets that will yield drugs with both increased efficacy anddecreased toxicity. RIT offers some advantages over other target-directed therapeutic modalities such as potent toxins or direct target

binding, and has recently undergone a surge of interest as moresophisticated drugs and targeted therapies have found success (30).There have been successes with RIT such as 90Y ibritumomab tiuxetan(Zevalin; Acrotech Biopharma, LLC), as well as radiolabeled peptidetherapies such as lutetium 177Lu dotatate (Lutathera; Advanced Accel-erator Applications USA, Inc.; ref. 31). However, it is a challengingdevelopment path; there are also failures, such as RIT directed againstCEA and MUC1, where early promising results have not yieldedeffective therapies (28, 29, 32). Success requires the right target,delivery vehicle, and therapeutic effector.

Cadherins represent a very attractive target due to their frequentoverexpression in a wide variety of tumors. Overexpression ofP-cadherin has been measured by both IHC and mRNA-based meth-ods in many tumor types, but because the literature on this subjectdescribes varying definitions and assay techniques, cross-study com-parisons of P-cadherin expression are difficult to perform andrequire cautious interpretation. Although the precise quantificationof P-cadherin in tumor tissues may not have universal agreement,P-cadherin clearly appears to be expressed in greater amounts than innormal tissue, particularly in epithelial tumors. It should be appre-ciated that nonepithelial tumors also overexpress cadherins, includingP-cadherin (9).

Strengthening the idea that P-cadherin is an important target, it isnotable that the majority of P-cadherin–directed therapies seem tohave good activity in preclinical models. Furthermore, because cad-herins interact with andmake up part of the tumormicroenvironment(TME), P-cadherin–directed therapymay complement other therapiesthat require TME alteration for greater effect. The elegant preclinicalwork reported by Zhang and colleagues also supports the role of theTME in tumor viability and progression (10). Despite these potentialadvantages, it should be noted that downregulation of P-cadherin maystimulate some malignant cell properties in certain settings (33).Therefore, although P-cadherin is an attractive target, as previouslymentioned, RIT therapy against the similarly attractive CEA andMUC1 led to disappointing results.

Here, we report the dose-escalation results of a first-in-humanclinical trial of an RIT targeting P-cadherin. These data represent thefirst reported clinical trial results of a P-cadherin–directed therapy.Descriptions of several antibody therapies directed against a cadherintarget have been previously published (9), but there have been nodefinitive results reported on their activity or safety in humans. Phase Istudies have been conducted with PF-06671008, a bispecific antibodyagainst both P-cadherin and CD3 (NCT02659631), as well as with twoadditional cadherin-directed antibody–drug conjugates, PCA-062

Table 3. 90Y-FF-21101–related adverse events in ≥ 2 patients.

Adverse event Total (n ¼ 16)a

Cohort 15 mCi/m2

(n ¼ 4)a

Cohort 210 mCi/m2

(n ¼ 3)

Cohort 315 mCi/m2

(n ¼ 3)

Cohort 420 mCi/m2

(n ¼ 3)

Cohort 525 mCi/m2

(n ¼ 3)

All Gr 3/4 All Gr 3/4 All Gr 3/4 All Gr 3/4 All Gr 3/4 All Gr 3/4Lymphopenia 11 (68.8%) 4 (25.0%) 0 0 3 1 3 1 3 2 2 0Leukopenia 5 (31.3%) 1 (6.3%) 0 0 0 0 2 0 2 1 1 0Thrombocytopenia 4 (25.0%) 1 (6.3%) 0 0 0 0 1 0 2 1 1 0Dysgeusia 3 (18.8%) 0 0 0 0 0 0 0 1 0 2 0AST, increased 2 (12.5%) 0 2 0 0 0 0 0 0 0 0 0Rash 2 (12.5%) 0 2 0 0 0 0 0 0 0 0 0

Note: None of the grade 3 or 4 adverse events were DLTs.Abbreviation: AST, aspartate aminotransferase.aOne patient received the 111In-FF-21101 dose only.

Subbiah et al.





(NCT02375958) and HKT288 (NCT02947152; ref. 34), directedagainst P-cadherin and Cadherin 6, respectively. Yoshioka and col-leagues reported preclinical data obtained from administration of aradioimmune-coupled mAb directed against P-cadherin, Mab-6 (35).Their preclinical data are strikingly similar to those reported for90Y-FF-21101; however, no further information has been made avail-able on the progression of the compound to human trials.

Coupled to a highly energetic (0.934 MeV mean and 2.28 MeVmaximum energies) beta emitter, 90Y-FF-21101 may offer advan-tages for targeting and affecting multiple tumor cells simultaneous-ly. With a mean emission penetration of only 4 mm, it requires onlymodest external radiation precautions. Preclinical data have alsopreviously demonstrated that the FF-21101 anti–P-cadherin anti-body appears to be preferentially taken up by tumors, withoutevidence of off-target toxicity or the formation of anti-drugantibodies (refs. 17, 18; Supplementary Figs S1–S3). In this clinicalstudy, 90Y-FF-21101 doses up to 25 mCi/m2 were found to be verywell tolerated in a heavily pretreated population of patients withadvanced solid tumors. Because P-cadherin is expressed in theretina, one safety concern was ophthalmologic effects; however,repeated ophthalmology evaluations revealed no ocular findings inany patient on study.

Dosimetric imaging revealed the organ with the highest radiotraceruptake was the spleen. As P-cadherin is a myo-epithelial antigen, thismay not have been anticipated. However, analysis of P-cadherinexpression in tumors and normal tissues demonstrates a moderateamount of P-cadherin expression in normal splenic tissue (mean �StdDev CDH3 mRNA transcripts per million, 15.8 � 10.2; Supple-mentary Fig. S1). Nonspecific binding as well asmacrophage uptake, aspreviously observed with some mAbs (36, 37), may also play a role inthe observed accumulation in the spleen, in addition to possibleaggregation/complexation. Variable accumulation of radioactivity inthe spleen as a consequence of variable aggregation could possiblyexplain the non-dose–related lymphopenia observed. Although theanalytic methodology used in this study was not capable of measuringaggregation, this, and complexation with ADA, remain potentialcontributing factors. Our clinical data to date demonstrates posttreat-ment ADA titers in only 2 patients, with one showing a relatively hightiter. Lack of measurable serum ADA could also be a function ofcomplexation of the circulating antibodywith low titer ADA, thereforeadditional evaluation is needed to further define this aspect of antibodyfate. On the basis of the serum protein pharmacokinetics, meanclearance and volume of distribution for the FF-21101 antibody wereconsistent with largely intravascular distribution, although someevidence of extravascular distribution is demonstrated by the rangeof individual distributional volumes. The Vss in our study wasdetermined using noncompartmental analysis. While reasonable forestimating a pharmacokinetic parameter, this type of model assumesall drug elimination occurs from the central compartment, which forantibodies that bind and internalize within cells in tissues sites, tends toalso overestimate the Vss.

Further analysis of the antibody pharmacokinetics showed themeasured t1/2 for the FF-21101 protein was 2.9 days, which is some-what less than some approved therapeutic chimeric monoclonal IgGantibodies, but is similar to the t1/2 for agents such as trastuzumab(2.7 days) and cetuximab (4.1 days). The half-life of IgG is 23 days, andits slow degradation is dependent on protection by FcRn binding to theFc portion of the antibody. FF-21101 may be cleared faster than othertherapeutic antibodies due to reduced affinity for the FcRn receptor.Other factors which may contribute to the increased elimination ofFF-21101 compared with other IgG-derived therapeutics include the

relative immunogenicity, the degree of glycosylation, and susceptibil-ity to proteolysis.

Localization of 111In-FF-21101 in tumor tissue in this study showeduptake in lesions in the majority of patients evaluated; however, bydesign, there were limitations for detailed evaluation of tumor target-ing.While thewhole-body anterior/posterior planar 111In scintigraphywas conducted on multiple days up to 144 hours post 111In-FF-21101administration, the SPECT/CT scan covering the lung, liver, andkidney regions was acquired only at one time point on day 2 (approx-imately 24 hours postinfusion), primarily to correct organ time–activity curves for attenuation and scatter, and mass-correct organradiation-absorbed doses. As illustrated by the lack of appreciableuptake observed in target axillary nodes in the ovarian cancer patientwho achieved a complete clinical response, assessment of tumortargeting can be challenging and complex, requiring three-dimensional imaging at multiple late time points for adequate contrastto assess smaller lesions, which was not performed in this study. Inaddition, the inherent sensitivity of gamma camera imaging fordetection of radioactivity in very small lesions and micrometastases,which are not uncommon, is low. Andwhile further assessment will bewarranted throughout the course of development, evidence of tumortargeting may not always be used as a future prerequisite for treatmentto proceed. As an example, the FDA eventually approved removalof pretreatment assessment of tumor uptake during the courseof development of Zevalin, due to its benefit in patients who wereknown to have disease but lacked visual evidence of uptake in111In-radioimmunoconjugate imaging.

In this initial phase I study enrollingmultiple types of solid tumors, adose response was not observed. However, as a first-in-human dose-escalation phase trial with a novel radioimmunoconjugate, this study isconsidered a signal-seeking study in patients with advanced andrefractory tumors, where lack of response may have been a conse-quence ofmultiple prior treatments and the refractoriness of advancedcancers. The response to therapy in our patient with clear cell ovariancancer despite reactivity was intriguing, and the high tumorP-cadherin expression in this tumor (H-score ¼ 242), one notcommonly associated with P-cadherin overexpression (38, 39), under-scores the importance of further evaluation of target expression as apotential correlate for activity. Although some patients with lowexpression maintained stable disease, the majority of patientswith longer term disease control had relatively high expression(H-score > 100).

Because of the need for more definitive assessment of antitumoractivity, the trial is now amended to evaluate defined tumor types for amore quantitative measure. Two expansion phase cohorts are beingevaluated, one for ovarian carcinoma and another for solid tumorsinclusive of triple-negative breast cancer, head and neck squamous cellcarcinoma, cholangiocarcinoma, pancreatic carcinoma, and colorectalcancer, at the recommended phase II administered activity of25 mCi/m2 (not exceeding 60 mCi/dose) every 3 months, withpotential for more frequent administration to be explored. All typesof ovarian carcinomas are eligible. These expansion cohorts will allowbetter characterization of safety, as well as provide more robustindications for a definitive trial of efficacy. Analysis of P-cadherinexpression continues to be performed for all patients in this expansionphase of development.

In summary, data from the dose escalation of 90Y-FF-21101 arepromising, but preliminary. As noted, patients received a variety ofdoses, a different number of doses, and had varying results. At thisearly stage, it is not possible to discern a definitive pattern of responsebased on P-cadherin expression score, tumor type, dose, or other






variables in this small number of patients. Much remains to beexplored, including, as noted above, the current schedule of treatmentevery 3–4 months, which is largely empirical. In the dose-escalationstudy, patients who received multiple (2–5) doses every 4 monthstolerated that schedule well, with cumulative activities that rangedfrom 40 to 100 mCi. More frequent dosing may be beneficial andappears to be promising for other radiopharmaceuticals such as thosebeing evaluated for treatment of prostate cancer (30). Investigation ofhigher dose levels may also be of value. A cautious limitation for doseescalation up to a maximum activity of 25 mCi/m2 was predefined inthis study based on estimates to remain below standard organ radiationdose limits typically used for external beam radiation therapy. How-ever, DLTs that have been observed at lower doses with other agents ofthis type, such as myelosuppression (24–28), were not observed with90Y-FF-21101 even at highest activity level. This improved safetymargin may reflect a more limited distribution of the target antigenin normal tissue, supporting the prospect for further escalation beyondthe initial recommended phase II activity level administered every3months. In addition, based on observations thus far that demonstrate90Y-FF-21101 is nonmyeloablative, there is potential for combinationwith other therapies including immunotherapy, targeted therapy, oreven chemotherapy. The favorable safety profile shown in this initialclinical dose-escalation study, alongwith some early signs of antitumoractivity, warrant further evaluation of this RIT approach.

Disclosure of Potential Conflicts of InterestV. Subbiah reports grants from Fujifilm (clinical trials research support)

during the conduct of the study; grants from Fujifilm outside the submittedwork; research funding/grant support for clinical trials from Roche/Genentech,Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Northwest Biothera-peutics, Berghealth, Incyte, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie,Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blue-print Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics,Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Ander-son Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals;travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, and Incyte;consultancy/advisory board relationships with Helsinn, Loxo Oncology/Eli Lilly,R-Pharma US, Incyte, QED Pharma, Medimmune, Novartis, and Signant Health;and other from Medscape. W.D. Erwin reports grants from Fujifilm Pharma-ceuticals U.S.A., Inc. during the conduct of the study, as well as grants fromOncosil Medical, Ltd., Ipsen Pharma SAS, and Alfasigma S.p.A. outside thesubmitted work. Q. Mawlawi reports grants from Fuji Pharmaceuticals duringthe conduct of the study. A. McCoy reports other from Fujifilm (study sponsor)during the conduct of the study. D. Wages reports personal fees from SalariusPharmaceuticals, Acerta Pharmaceuticals, and Novella outside the submittedwork. C. Gonzalez-Lepera reports grants from Fujifilm (grant to produce thedrug in-house) during the conduct of the study. H.A. Macapinlac reports grantsfrom Fujifilm during the conduct of the study. F. Meric-Bernstam reports personalfees from Aduro BioTech Inc. (consulting), Alkermes (consulting), DebioPharm(consulting), F. Hoffman-La Roche Ltd. (consulting), Jackson Laboratory (con-sulting), Kolon Life Science (consulting), OrigiMed (consulting), PACT Pharma(consulting), Parexel International (consulting), Pfizer Inc. (consulting), SamsungBioepis (consulting), Seattle Genetics Inc. (consulting, advisory committee), TyraBiosciences, Xencor, Zymeworks, Immunomedics, Inflection Biosciences, Mer-sana Therapeutics, Spectrum Pharmaceuticals (advisory committee), and Zentalis(advisory committee), grants and personal fees from Effector Therapeutics(consulting, sponsored research), Genentech Inc. (consulting, sponsoredresearch), IBM Watson (consulting), Puma Biotechnology Inc. (sponsoredresearch, advisory board), and Silverback Therapeutics (advisory committee),grants from Aileron Therapeutics (sponsored research), AstraZeneca (sponsoredresearch), Bayer Healthcare Pharmaceutical (sponsored research), CalitheraBiosciences (sponsored research), Curis Inc. (sponsored research), CytomXTherapeutics Inc. (sponsored research), Daiichi Sankyo Co. Ltd. (sponsoredresearch), Debiopharm International (sponsored research), Guardant Health Inc.(sponsored research), Millennium Pharmaceuticals (sponsored research), Novar-tis (sponsored research), and Taiho Pharmaceutical Co. (sponsored research),

non-financial support from Chugai Biopharmaceuticals (honoraria - speakingengagement), Mayo Clinic, and Rutgers Cancer Institute of New Jersey, and otherfrom Beth Israel Deaconess Medical Center (travel related) outside the submittedwork. D.S. Hong reports grants and other from Pfizer (research support to MDAnderson) outside the submitted work; research/grant funding from AbbVie,Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, 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 Ther-apeutics; travel and accommodation expense support from Bayer, LOXO, miRNA,Genmab, AACR, ASCO, and SITC; consulting or advisory roles at Alpha Insights,Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H,Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, PrimeOncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; and otherownership interests in MolecularMatch (advisor), OncoResponse (founder), andPresagia Inc (advisor). D.B. Le reports grants from Fujifilm (to the institution)during the conduct of the study. T. Suzuki reports other from Fujifilm Pharma-ceuticals U.S.A., Inc. (employed) during the conduct of the study, as well as otherfrom Fujifilm Pharmaceuticals U.S.A., Inc. (employed) outside the submittedwork. R.A. Subach was a consultant to Fujifilm Pharmaceuticals U.S.A., Inc. until5/28/2020 and was hired by Fujifilm Pharmaceuticals U.S.A., Inc. on 5/29/2020and is currently employed full time. F. Nomura reports grants from Fujifilmduring the conduct of the study and a patent for JP5380553 licensed to Fujifilm,and is engaged in a job in Perseus Proteomics Inc (Perseus Proteomics was asubsidiary company under parent company Fujifilm until 2018); Fujifilm sup-ported preclinical and clinical research with other subsidiary brother companies:Fujifilm RI Pharma (currently named Fujifilm Toyama Chemical), etc. T. Mat-suura reports grants from Fujifilm during the conduct of the study, a patent forJP5380553 licensed to Fujifilm, and engagement in a job in Perseus ProteomicsInc. (Perseus Proteomics was a subsidiary company under parent companyFujifilm until 2018); Fujifilm supported preclinical and clinical research withother subsidiary brother companies: Fujifilm RI Pharma (currently namedFujifilm Toyama Chemical), etc. M. Kajita reports a grant from Fujifilm Corpo-ration during the conduct of the study and outside the submitted work. E.Nakamura reports a grant from Fujifilm Corporation during the conduct of thestudy and outside the submitted work. Y. Funase reports a grant from FujifilmCorporation during the conduct of the study and outside the submitted work.G. Ravizzini reports grants from Fujifilm during the conduct of the study andoutside the submitted work. No potential conflicts of interest were disclosed bythe other authors.

Authors’ ContributionsV. Subbiah: Conceptualization, resources, formal analysis, supervision, funding

acquisition, validation, investigation, methodology, writing-original draft, projectadministration, writing-review and editing.W. Erwin: Conceptualization, resources,data curation, software, formal analysis, methodology, writing-review and editing.O. Mawlawi: Resources, investigation, visualization. A. McCoy: Data curation,validation. D. Wages: Formal analysis, investigation, writing-original draft,writing-review and editing. C. Wheeler: Formal analysis, investigation.C. Gonzalez-Lepera: Validation, investigation. H. Liu: Investigation,methodology. H. Macapinlac: Supervision, methodology, project administration.F. Meric-Bernstam: Resources, funding acquisition, investigation, methodology,project administration. D. Hong: Resources, investigation, writing-original draft.S. Pant: Resources, investigation. D. Le: Resources, supervision, projectadministration. E. Santos: Data curation, software, formal analysis. J.F. Gonzalez:Resources, data curation, formal analysis. J. Roszik: Software, formal analysis,validation. T. Suzuki: Formal analysis, investigation, resources, writing-originaldraft. R. Subach: Formal analysis, project administration. T. Madden: Datacuration, formal analysis, supervision, investigation, methodology, validation,writing-original draft. M. Johansen: Data curation, formal analysis, investigation,writing-review and editing. F. Nomura: Conceptualization, resources, data curation,validation, visualization.H. Satoh: Conceptualization, data curation, formal analysis,funding acquisition, validation, methodology. T. Matsuura: Conceptualization, datacuration, software, formal analysis, project administration.M. Kajita: Data curation,formal analysis, funding acquisition. E. Nakamura: Resources, formal analysis,funding acquisition, visualization. Y. Funase: Resources, formal analysis.S. Matsushima: Resources, data curation, formal analysis. G. Ravizzini:Conceptualization, resources, data curation, formal analysis, supervision,validation, investigation, visualization, methodology, writing-original draft, projectadministration, writing-review and editing.

Subbiah et al.





AcknowledgmentsThe study was funded by FUJIFILM Pharmaceuticals U.S.A., Inc. The authors

acknowledge the patients and their families for participating in this radiophar-maceutical first-in-human clinical trial. V. Subbiah is supported by NIH/NCIgrant 1R01CA242845-01A1. This work was supported in part by The CancerPrevention and Research Institute of Texas (RP1100584), the Sheikh Khalifa BinZayed Al Nahyan Institute for Personalized Cancer Therapy, 1U01 CA180964,NCATS grant UL1 TR000371 (Center for Clinical and Translational Sciences),and The MD Anderson Cancer Center support grant (P30 CA016672). Thefunders had no role in the design of the study; the collection, analysis, and

interpretation of the data; the writing of the manuscript; or the decision to submitthe manuscript for publication.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received January 4, 2020; revised April 26, 2020; accepted August 14, 2020;published first August 18, 2020.

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Subbiah et al.




2020;26:5830-5842. Published OnlineFirst August 18, 2020.Clin Cancer Res Vivek Subbiah, William Erwin, Osama Mawlawi, et al. Y-FF-21101 Monoclonal Antibody in Solid Tumors

90targeted Radioimmunotherapy with −Phase I Study of P-cadherin

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