1124TiP Randomized, Phase II Study of Ficlatuzumab With or Without Cetuximab in Patients With Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Julie E. Bauman,1 Simran Sindhu,2 Denise Roe,3 Nabil F. Saba,4 Jessica R. Bauman,5 Christine H. Chung,6 Jessica L. Geiger,7 Aarti Bhatia,8 Steven Wang,9 Audrey Baker,9 Shethal Bearelly,9 Carlos Caulin,1 Protul Shrikant,9 Barbara Burtness,8 and Panayiotis Savvides1 1The University of Arizona Cancer Center, Tucson, AZ, USA; 2Banner University Medical Center, Tucson, AZ, USA; 3Mel & Enid Zuckerman College of Public Health, The University of Arizona Cancer Center, Tucson, AZ, USA; 4Emory University Winship Cancer Institute, Atlanta, GA, USA; 5Fox Chase Cancer Center, Philadelphia, PA, USA; 6H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 7Cleveland Clinic, Cleveland, OH, USA; 8Yale Cancer Center, New Haven, CT, USA; 9University of Arizona Cancer Center, Phoenix, AZ, USA • Response assessment will be as follows: • History of second malignancy within 2 years before study day 1 (with the exception Background Study Hypothesis – Response and progression will be evaluated every 8 weeks using the revised Response Inclusion/Exclusion Criteria of excised and cured non-melanoma skin cancer, carcinoma in situ of breast or cervix, Evaluation Criteria in Solid Tumors (RECIST) version 1.1 superficial bladder cancer, stage I differentiated thyroid cancer that is resected or • Roughly 90% of all head and neck cancers are squamous cell carcinomas (HNSCC), • Inhibition of the HGF/c-Met pathway may overcome resistance to EGFR therapy – Measurable disease (Table 1) will be defined by the presence of ≥1 measurable lesion Key Inclusion Criteria observed, or pT1a /pT1b prostate cancer comprising <5% of resected tissue with which is the sixth leading cancer by incidence worldwide1 and provide an important clinical benefit in patients with R/M HNSCC that can be accurately measured in ≥1 dimension as ≥20 mm (for neck lymph nodes; normal prostate-specific antigen since resection, or cT1a/cT1b prostate cancer treated ≥15 mm) • Adults aged 18 years with brachytherapy or external beam radiation therapy with normal PSA since radiation) – Despite advances in multimodality therapy, 5-year overall survival (OS) is approximately • The cetuximab and ficlatuzumab combination or ficlatuzumab alone can improve 60% and has increased only incrementally in the past 2 decades2 the median PFS from the historical control of 2 months to 3.3 months (a 60% – Changes in the largest diameter (unidimensional measurement) of tumor lesions and the • Consent to a research biopsy of tumor tissue at baseline • Major surgery within 6 weeks before study day 1 improvement) in patients with R/M HNSCC shortest diameter in the case of malignant lymph nodes will be used – Patients with recurrent/metastatic (R/M) HNSCC have a particularly poor prognosis, • ECOG PS 0 or 1 at the time of informed consent • HIV-positive patients receiving combination antiretroviral therapy with a median OS of 6 to 10 months2 – Target lesions will be identified as all measurable lesions (up to a maximum of 2 per organ, and 5 lesions in total) and evaluated as complete response (CR), partial response • Measurable disease per RECIST version 1.1 criteria • Pregnant or breastfeeding women • To date, the only targeted therapy to treat HNSCC is cetuximab, an anti-epithelial Study Design (PR), PD, or stable disease (SD) • Histologically confirmed HNSCC from any primary site growth factor receptor (EGFR) monoclonal antibody (mAb)3 – Measurement of non-target lesions will not be required, but the presence or absence of • R/M disease, fulfilling ≥1 of the following criteria: – EGFR is a transmembrane glycoprotein receptor kinase (RTK) that initiates a • This study (NCT03422536) is an investigator-sponsored, randomized, noncomparative, each will be noted throughout the duration of follow-up Statistical Methods pleiotropic network of downstream signaling cascades, effecting cellular proliferation multicenter, 2-arm phase 2 trial of ficlatuzumab monotherapy and ficlatuzumab plus – Incurable disease (as assessed by surgical or radiation oncology) and angiogenesis cetuximab combination therapy in patients with R/M HNSCC after failure of cetuximab – Metastatic disease • The primary objective is to estimate PFS in both study arms compared with an historical (Figure 2) Table 1. Evaluation for patients with measurable disease control of 2 months represented by dealer’s choice chemotherapy in the phase 3 trial – Despite aberrant signaling in HNSCC, primary or acquired resistance to cetuximab is – Persistent or progressive disease following curative-intent radiation inevitable, initiating interest in understanding resistance mechanisms by which to drive (ie, target disease) of nivolumab in platinum-refractory HNSCC; both arms will be will be tested for a novel therapeutic options for this patient population Figure 2. Study design • Cetuximab resistant, fulfilling ≥1 of the following criteria: 60% increase of PFS from a median of 2 months to 3.33 months Best overall response Target Non-target New Overall – PFS will be tested using a log-rank test with 90% power while assuming a 0.10 one-sided • An established resistance mechanism to anti-EGFR therapy is activation of when confirmation – Disease persistence or recurrence within 6 months of completing definitive radiotherapy lesions lesions lesions response type 1 error rate alternative RTKs, including c-Met, the hepatocyte growth factor (HGF) receptor is required for locally advanced disease (radiation must have included concurrent cetuximab; Primary: induction chemotherapy may or may not have included cetuximab) – 66 patients (33 for ficlatuzumab, 33 for ficlatuzumab/cetuximab) with a total of 33 events 4 Ficlatuzumab 20 mg/kg Q2W – c-Met and/or HGF are overexpressed in approximately 80% of HNSCC (Figure 1) R PFS CR CR No CR ≥4 weeks confirmationa per arm will be required A – Disease progression during or within 6 months of cetuximab treatment in the R/M setting – Data have shown that HGF/c-Met inhibition may overcome resistance to anti-EGFR • R/M HNSCC N – Assuming a dropout percentage of 10%, 74 patients in total will be accrued to obtain the 5-9 D therapy in R/M HNSCC • ECOG PS 0-1 CR Non-CR/non-PD No PR – Prior cetuximab exposure (any line of therapy) necessary 66 eligible randomized patients O • Clinical resistance to M Ficlatuzumab 20 mg/kg Q2W + – Enrollment will take 24 months, with an additional follow-up of 6 months (making the study 2 Secondary: • Platinum-resistant or platinum-ineligible, fulfilling ≥1 of the following criteria: Figure 1. c-Met and HGF overexpression in HNSCC4 anti-EGFR therapy I cetuximab 500 mg/m CR Not evaluated No PR ≥4 weeks confirmationa duration approximately 2.5 years) Z toxicity, QoL, RR, OS, prognostic biomarker – Disease persistence or recurrence within 6 months of completing definitive radiotherapy for E Non-CR/non-PD/ – If both arms achieve the hypothesized PFS, the numerically superior arm will be advanced A B C assessment PR No PR locally advanced disease, where platinum chemotherapy was administered as a not evaluated to phase 3 testing 250 15 component of induction and/or concurrent systemic treatment Continuous treatment until PD P < 0.01 • PFS and OS will be estimated for each arm using a Kaplan-Meier estimates 200 Documented at least – Disease progression within 6 months of treatment with platinum chemotherapy Non-CR/non-PD/ 10 SD No SD once ≥4 weeks from 150 not evaluated • Toxicity and RR will be reported with an exact 95% CI baseline – Deemed as an unacceptable candidate for platinum chemotherapy (as assessed by 100 the local investigator) 5 • The relationship between PFS and candidate biomarkers will be assessed using Cox Frequency ECOG PS, Eastern Cooperative Oncology Group performance status; RR, response rate; PD, progressive disease; QoL, PD Any Yes or no PD HGF HGF Score IHC 50 quality of life. – Prior platinum exposure (any line of therapy) proportional hazards 0 0 – Baseline VeriStrat, HGF/c-Met dimers, and baseline pMet will be tested at Any PDb Yes or no PD No prior SD, PR, or CR • If eligible for immunotherapy, patients must have prior immunotherapy exposure Adj. Mucosa Tumor 0 50 100 150 200 • Patients will be randomized in a 1:1 ratio (ficlatuzumab/ficlatuzumab and cetuximab) and (anti-PD-1 or anti-PD-L1) α = 0.05 in order to guarantee a maximum 15% false discovery rate Tissue Type Tumor HGF IHC Score stratified by Any Any Yes PD – Prior exposure to investigational immunotherapies (including anti-CTLA-4, anti-OX40, • Other candidate biomarkers will be quantitatively measured and evaluated as predictors 250 30 – Human papillomavirus (HPV) status: HPV-positive HNSCC will be assessed by p16 status anti-CD40, anti-CD27, and anti-TNFR antibodies) is also considered acceptable of PFS and/or tumor response in generalized linear models P = 0.04 performed per standard of care at the local site; patients must meet both of the following aOnly for nonrandomized trials with response as the primary endpoint. bIn exceptional circumstances, unequivocal 200 25 – Calculated P values for testing the significance of prediction models will be adjusted for criteria: 1) either oropharynx or unknown primary site; and 2) p16+ by IHC where ≥70% progression in non-target lesions may be accepted as disease progression. • Within 28 days of registration, the following laboratory values must be measured: 20 false discovery using the Benjamini and Hochberg