Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

Exceptional response to cetuximab monotherapy after failure of immunotherapy with a checkpoint inhibitor in a patient with metastatic head and neck squamous cell cancer: case report and review of the literature.

Immunotherapy with PD-1 inhibitors monotherapy or combined with chemotherapy comprises the first-line palliative treatment for patients with recurrent or metastatic head and neck squamous cell cancers (R/M HNSCC). The established survival advantage among responders is overshadowed by the high percentage of patients failing the standard PD-1 inhibitor-based treatments. Salvage therapies are direly needed. However, no current standards are available. We present the case of a 65-year-old patient with heavily pretreated laryngeal squamous cell carcinoma who had an exceptional response to cetuximab monotherapy following the failure of immunotherapy with the PD-1 inhibitor nivolumab. We reviewed the literature for other cases of exceptional response to cetuximab, clinical studies investigating the combined or sequential administration of cetuximab and PD-1 inhibitors, and the mechanistic rationale for consideration of cetuximab as a potential salvage treatment after immunotherapy with PD-1 inhibitors. In addition to the specific epidermal growth factor receptor inhibitory effect, cetuximab, as an immunoglobulin G1 isotype, binds NK cells and elicits antibody-dependent cellular toxicity, triggering a domino of immunostimulatory, and immunoinhibitory effects that actually might decrease the cetuximab anticancer efficacy. However, in a tumor microenvironment exposed to previous treatment with a PD-1 inhibitor, the effects of the PD-1 inhibitor followed by cetuximab on innate and adaptative immune response appear to synergize. Specifically, persistent immune checkpoint inhibitors' consequences may negate downstream immunosuppressive effects of cetuximab caused through PD-1/PD-L1 upregulation, making it a more potent treatment option. Besides the potential synergistic effect on antitumor immune response with previous immune checkpoint inhibitors therapy, cetuximab is the only targeted agent approved for treating R/M HNSCC, making it a most advantageous candidate for further treatment validation studies as salvage treatment post-immunotherapy.

Utility of a nitinol stone extractor for intraocular foreign body removal.

Purpose: To describe the novel application of a urological instrument, the nitinol stone basket, in the removal of a retained intraocular foreign body (IOFB). Observations: This is a retrospective case series describing two eyes of two patients presenting with metallic IOFBs after hammering metal-on-metal. Both patients underwent 23-gauge pars plana vitrectomy (PPV) and successful IOFB extraction using the NCircle® Nitinol Tipless Stone Extractor. There were no intraoperative or post-surgical complications. Both patients demonstrated improvement in vision, with most recent postoperative visual acuities of 20/40 and 20/60. Conclusions and importance: The nitinol stone basket may be considered for removal of IOFBs, particularly larger IOFBs that are difficult to grasp with forceps. Our cases add to the literature showing favorable visual outcomes and few complications in the post-operative period using this technique.

A Rare Case of Hereditary Hemochromatosis Presenting With Porphyria Cutanea Tarda.

Hereditary hemochromatosis is an autosomal recessive condition with incomplete penetrance that is most commonly caused by a mutation in the HFE gene. Hereditary hemochromatosis can remain asymptomatic in some patients until triggered by certain events. Porphyria cutanea tarda is a condition that can lead to iron overload due to defective synthesis of heme and can cause the onset of adult-onset hereditary hemochromatosis. Herein, we present a case where a 77-year-old man presented with painful blisters on the sun-exposed areas of his hands and was diagnosed with porphyria cutanea tarda. Further testing for mutations in the HFE gene given elevated ferritin was performed and returned positive, which confirmed the diagnosis of adult-onset hereditary hemochromatosis. The patient received serial therapeutic phlebotomy for iron overload and adopted lifestyle modifications such as avoiding sun exposure of upper extremities. The patient's blisters and laboratory iron panel parameters improved with continued phlebotomy. Therapeutic phlebotomy has been demonstrated to be an effective first-line therapy in patients with dual diagnosis. Our case highlights that cutaneous symptoms due to porphyria cutanea tarda may be the first presenting symptom in patients with underlying hemochromatosis.

Effectiveness and toxicity of cetuximab with concurrent RT in locally advanced cutaneous squamous cell skin cancer: a case series.

BACKGROUND: Treatment for locally advanced cutaneous squamous cell cancers (laCSCC) remains poorly defined. Most laCSCC tumors express high levels of epidermal growth factor receptors (EGFR). Cetuximab has activity in other EGFR expressing cancers and enhances the effectiveness of radiotherapy. METHODS: A retrospective review of institutional data identified eighteen patients with laCSCC treated with cetuximab induction and concurrent radiotherapy. The loading dose of cetuximab was 400 mg/m² IV. Subsequent weekly doses of 250 mg/m² IV were infused throughout the period of radiation. The treatment doses ranged from 4500-7000 cGy, with a dose fraction of 200-250 cGy. RESULTS: The objective response rate was 83.2% with 55.5% complete responses and 27.7% partial responses. Median progression-free survival was 21.6 months. Progression-free survival was 61% at 1 year and 40% at 2 years. With longer follow-up, some patients developed a local recurrence (16.7%), distant metastases (11.1%) or a second primary cancer (16.3%). Cetuximab was well tolerated, with 68.4% patients experienced only mild acneiform skin rash or fatigue (Grade 1 or 2). Radiotherapy produced expected side effects (skin erythema, moist desquamation, mucositis). DISCUSSION: Cetuximab plus radiotherapy represents an active and tolerable treatment option for laCSCC, including patients with contraindications for checkpoint inhibitor therapy.

Genomic and Transcriptomic Predictors of Response from Stereotactic Body Radiation Therapy in Patients with Oligoprogressive Renal Cell Carcinoma.

Stereotactic body radiation therapy (SBRT) has been shown to be safe and effective for delaying systemic treatment change among patients with metastatic renal cell carcinoma (mRCC). In this study, we sought to assess the genomic signatures of patients with mRCC who underwent SBRT for oligoprogression. A total of 30 patients with oligoprogressive disease were identified, the majority of whom had clear cell renal cell carcinoma (83.3%) and were receiving first-line treatment (53.3%). Genomic and transcriptomic sequencing were available in 20 and 16 patients, respectively. Duration of systemic treatment (DOT) was categorized as that prior (DOT[P]) and subsequent (DOT[S]) to radiation treatment. The median DOT(P) and DOT(S) were 15.1 and 18.3 mo, respectively, with a median DOT(S)/DOT(P) ratio of 1.4. Patients who had a DOT(S)/DOT(P) ratio of ≥1 had increased expression in pathways related to cell proliferation and development. In contrast, among patients with a ratio of ≤1, the reactive oxygen species pathway was enriched. This study highlights the potential role of genomics and transcriptomics to refine radiation treatment selection in patients with mRCC. PATIENT SUMMARY: In this study, we looked at mutations and genomic expressions among kidney cancer patients who responded better to stereotactic body radiotherapy. We found that enriched expression of certain pathways might play a role in response to radiotherapy.

Oculomotor Nerve Palsy as a Manifestation of Immune Thrombocytopenic Purpura: A Case Report.

Immune thrombocytopenic purpura (ITP) is caused by alterations in the immune system resulting in platelet destruction. It often manifests clinically with bleeding or on routine lab work revealing thrombocytopenia in asymptomatic individuals. Neurologic manifestations of this condition are sparsely documented in the literature. Among the symptoms reported were case reports of ischemic strokes, transient ischemic attacks, mononeuropathy multiplex, and polyneuropathy as neurological complications from immune thrombocytopenic purpura. Isolated cranial nerve palsies are uncommon. The following case describes a patient with immune thrombocytopenic purpura who presented with an isolated cranial nerve III palsy. A 55-year-old presented with pain in the right eye that was found in a downward and lateral gaze paralysis. There was no evidence of central or peripheral neurovascular etiology on imaging. However, workup revealed isolated thrombocytopenia with platelets <2000/ml3. Other possible etiologies, such as human immunodeficiency virus (HIV) and infectious etiologies, were evaluated and excluded. Thrombotic thrombocytopenia purpura was excluded with the results from ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. The patient was appropriately transfused with platelets and was treated with methylprednisolone, which improved his platelets. At the time of discharge, the patient continued to have cranial nerve III palsy and was referred to follow up with hematology on an outpatient basis. In prior case reports where ITP presented as neurological deficits, there was evidence of intraneural microhemorrhage. Our case is unique in that the primary neurologic presentation without central nervous system pathology eventually led to the diagnosis of ITP. The symptoms were attributed to microhemorrhages that were not detected in imaging studies. Further studies are warranted to explore any correlation or causative association between ITP and neurological symptoms. This case report highlights the need to consider uncommon but possible manifestations of conditions that may initially appear seemingly irrelevant to the patient's chief complaint.

Serendipitous synergism - an exceptional response to treatment with pembrolizumab in the course of a natural immunovirotherapy: a case report and review of the literature.

Immune checkpoint inhibitors (ICIs) are the current guideline recommended treatment for many malignancies considered to be terminal. Despite considerable advances, their utility remains limited, and the field requires synergistic partners to further improve outcomes. Oncolytic viruses (OV) are emerging as contenders for the role of the synergistic agent of choice due to their multi-mechanistic effect on activating the tumor 'cold' immune microenvironment. Herpes simplex virus 1, a naturally selective OV, is the most advanced virotherapeutic compound in clinical applications for use in combination with ICI. We here present the case of a 72 year-old patient with a heavily pre-treated, advanced maxillary sinus squamous cell cancer with distant metastases who developed complete response (CR) with only three administrations of a programmed death 1 inhibitor after treatment interference by a severe herpes zoster infection, based on the related alpha-herpesvirus varicella zoster virus (VZV). This exceptional response has been followed and confirmed with imaging studies over more than 5 years. Although the patient had several favorable predictors for response to immunotherapy, we reason that the exceptional response may in part be secondary to the serendipitous VZV infection. Documented cases of cancer patients that achieved CR after few administrations of treatment with ICI are rare, with most reporting follow up of just over 1 year or less. In this case, it is conceivable that the interference of the infection with VZV, soon after the start of immunotherapy with ICI, led to a lasting antitumor immunity and sustained CR. This hypothesis is supported by the concept of 'oncolytic immunotherapy' which is reviewed in this manuscript. In addition, persistence of a TP53 mutation found in a liquid biopsy, despite clinical and radiologic remission, is discussed.

Lower Fracture Rates in Patients Treated with Radium-223, Abiraterone or Enzalutamide, When Given Concurrently with Bone Health Agents: A Real-World Analysis.

BACKGROUND: The phase 3 trial ERA223 demonstrated an increased fracture rate and no survival advantage for metastatic castration resistant prostate cancer (mCRPC) patients on Radium-223 (Ra-223) with abiraterone, leading to regulatory restrictions on combination therapy. However, less than half of trial patients received bone health agents (BHA). We reviewed electronic health record (EHR) data evaluating fracture rates for patients on BHA receiving Ra-223, androgen deprivation therapy and either abiraterone or enzalutamide. PATIENTS AND METHODS: We conducted a retrospective, cohort analysis of EHR data of mCRPC patients on Ra-223 treated at a single community center by a single provider between 2010 and 2018. The primary objective was evaluating fracture rates for patients on BHA receiving Ra-223 and abiraterone. We conducted a secondary analysis for enzalutamide. RESULTS: One hundred seventy-seven patients received Ra-223 concurrently with abiraterone or enzalutamide between November 2010 and August 2018. The median age was 73 at first Ra-223 dose (range 40-93). The median follow-up time from last Ra-223 dose was 30 months (range 2-106). One hundred sixty-four patients (93%) received BHAs. One hundred fifty-nine patients (89%) were on a BHA before and/or during Ra-223. Sixty-seven patients received denosumab (38%), 63 received zoledronic acid (36%), and 29 received both nonconcurrently (16%). Eleven patients (6.2%) experienced a fracture after starting Ra-223, 9 of which occurred while on prior and/or concurrent BHA. We observed a 5.7% fracture rate for mCRPC patients who received combination therapy and denosumab or zoledronic acid. CONCLUSION: This real-world analysis demonstrating a low fracture rate in patients with mCRPC receiving a BHA while on Ra-223 and abiraterone or enzalutamide may inform current clinical practice.

Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer.

Virus positive Merkel cell carcinoma (VP-MCC) is an aggressive but immunogenic skin malignancy driven by Merkel cell polyomavirus (MCPyV) T antigen (TAg). Since adoptive T cell transfer (ACT) can be effective against virus-driven malignancies, we set out to develop a methodology for generating MCPyV TAg specific T cells. MCPyV is a common, asymptomatic infection and virus-exposed healthy donors represent a potential source of MCPyV TAg specific T cells for ACT. Virus specific T cells were generated using monocyte-derived dendritic cells (moDCs) pulsed with MCPyV TAg peptide libraries and co-cultured with autologous T cells in supplemented with pro-inflammatory and homeostatic cytokines for 14 days. Specific reactivity was observed predominantly within the CD4+ T cell compartment in the cultures generated from 21/46 random healthy donors. Notably, responses were more often seen in donors aged 50 years and older. TAg specific CD4+ T cells specifically secreted Th1 cytokines and upregulated CD137 upon challenge with MCPyV TAg peptide libraries and autologous transduced antigen presenting cells. Expanded T cells from healthy donors recognized epitopes of both TAg splice variants found in VP-MCC tumors, and minimally expressed exhaustion markers. Our data show that MCPyV specific T cells can be expanded from healthy donors using methods appropriate for the manufacture of clinical grade ACT products.

Stepwise progressive parametric multiple testing procedure with correlated normal test statistics.

Multiple testing problems are often seen in clinical trials. An appropriate testing procedure should be specified to deal with the potential inflation of type I error rate due to multiplicity. In this article, we propose a stepwise progressive parametric multiple (SPPM) testing procedure, which constructs the testing using the products of all the combinations of local [Formula: see text]-values and the critical values are determined by numerical integrations progressively using the closure principle. We have compared the performance of SPPM to several other procedures, and demonstrate the advantage of SPPM procedure, in terms of power, for the certain situations of multiple testing.

Restoring antiviral immunity with adoptive transfer of ex-vivo generated T cells.

PURPOSE OF REVIEW: Latent viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus (ADV) often reactivate in immunocompromised patients, contributing to poor clinical outcomes. A rapid reconstitution of antiviral responses via adoptive transfer of virus-specific T cells (VSTs) can prevent or eradicate even refractory infections. Here, we evaluate this strategy and the associated methodological, manufacturing and clinical advances. RECENT FINDINGS: From the early pioneering but cumbersome efforts to isolate CMV-specific T cell clones, new approaches and techniques have been developed to provide quicker, safer and broader-aimed ex-vivo antigen-specific cells. New manufacturing strategies, such as the use of G-Rex flasks or 'priming' with a library of overlapping viral peptides, allow for culturing greater numbers of cells that could be patient-specific or stored in cell banks for off-the-shelf applications. Rapid isolation of T cells using major histocompatibility complex tetramer or cytokine capture approaches, or genetic reprogramming of cells to target viral antigens can accelerate the generation of potent cellular products. SUMMARY: Advances in the ex-vivo generation of VSTs in academic medical centres and as off-the-shelf blood bank-based or commercially produced reagents are likely to result in broader accessibility and possible manufacturing cost reduction of these cell products, and will open new therapeutic prospects for vulnerable and critically ill immunocompromised patients.

Example-based illustrations of design, conduct, analysis and result interpretation of multi-regional clinical trials.

Extensive research has been conducted in the Multi-Regional Clinical Trial (MRCT) area. To effectively apply an appropriate approach to a MRCT, we need to synthesize and understand the features of different approaches. In this paper, examples are used to illustrate considerations regarding design, conduct, analysis and interpretation of result of MRCTs. We start with a brief discussion of region definitions and the scenarios where different regions have differing requirements for a MRCT. We then compare different designs and models as well as the corresponding interpretation of the results. We highlight the importance of paying special attention to trial monitoring and conduct to prevent potential issues associated with the final trial results. Besides evaluating the overall treatment effect for the entire MRCT, we also consider other key analyses including quantification of regional treatment effects within a MRCT, and assessment of consistency of these regional treatment effects.

Unified additional requirement in consideration of regional approval for multiregional clinical trials.

To speed up the process of bringing a new drug to the market, more and more clinical trials are being conducted simultaneously in multiple regions. After demonstrating the overall drug's efficacy across regions, the regulatory and drug sponsor may also want to assess the drug's effect in specific region(s). Most of the recent approaches imposed a uniform criterion to assess the consistency of treatment effects between the interested region(s) and the entire study population regardless of the number of regions in multiregional clinical trials (MRCT). As a result, the needed sample size to achieve the desired probability of satisfying the regional requirement could be huge and implausible for the trial sponsors to implement. In this paper, we propose a unified additional requirement for regional approval by differing the parameters in the additional requirement depending on the number of planned regions. In particular, the values of the parameters are determined by a reasonable sample size increase with the desired probability satisfying the additional requirement. Considering the practicality of the global trial or sample size increase, we recommend specific values of the parameters for a different number of planned regions. We also introduce the assurance probability curve to evaluate the performance of different regional requirements.

What Constitutes Science and Scientific Evidence: Roles of Null Hypothesis Testing.

We briefly discuss the philosophical basis of science, causality, and scientific evidence, by introducing the hidden but most fundamental principle of science: the similarity principle. The principle's use in scientific discovery is illustrated with Simpson's paradox and other examples. In discussing the value of null hypothesis statistical testing, the controversies in multiple regression, and multiplicity issues in statistics, we describe how these difficult issues should be handled based on our interpretation of the similarity principle.

Systematic comparison of the statistical operating characteristics of various Phase I oncology designs.

Dose finding Phase I oncology designs can be broadly categorized as rule based, such as the 3 + 3 and the accelerated titration designs, or model based, such as the CRM and Eff-Tox designs. This paper systematically reviews and compares through simulations several statistical operating characteristics, including the accuracy of maximum tolerated dose (MTD) selection, the percentage of patients assigned to the MTD, over-dosing, under-dosing, and the trial dose-limiting toxicity (DLT) rate, of eleven rule-based and model-based Phase I oncology designs that target or pre-specify a DLT rate of ∼0.2, for three sets of true DLT probabilities. These DLT probabilities are generated at common dosages from specific linear, logistic, and log-logistic dose-toxicity curves. We find that all the designs examined select the MTD much more accurately when there is a clear separation between the true DLT rate at the MTD and the rates at the dose level immediately above and below it, such as for the DLT rates generated using the chosen logistic dose-toxicity curve; the separations in these true DLT rates depend, in turn, not only on the functional form of the dose-toxicity curve but also on the investigated dose levels and the parameter set-up. The model based mTPI, TEQR, BOIN, CRM and EWOC designs perform well and assign the greatest percentages of patients to the MTD, and also have a reasonably high probability of picking the true MTD across the three dose-toxicity curves examined. Among the rule-based designs studied, the 5 + 5 a design picks the MTD as accurately as the model based designs for the true DLT rates generated using the chosen log-logistic and linear dose-toxicity curves, but requires enrolling a higher number of patients than the other designs. We also find that it is critical to pick a design that is aligned with the true DLT rate of interest. Further, we note that Phase I trials are very small in general and hence may not provide accurate estimates of the MTD. Thus our work provides a map for planning Phase I oncology trials or developing new ones.

Biomarker informed add-arm design for unimodal response.

In this article, we propose a biomarker informed add-arm design for unimodal response. The new design contributes to optimizing the procedure of dose-finding when a biomarker of the study primary endpoint exists and prior evidence indicates a unimodal dose-response relationship. Designs with up to seven active treatment arms were considered. We propose the statistical approach for the Type I error control and carry out extensive simulation studies for the power performance of the design. The proposed design is shown to outperform the corresponding biomarker informed two-stage winner design in power on an average.

The Add-Arm Design for Unimodal Response Curve with Unknown Mode.

In a classical drop-loser (or drop-arm) design, patients are randomized into all arms (doses) and at the interim analysis, inferior arms are dropped. Therefore, compared to the traditional dose-finding design, this adaptive design can reduce the sample size by not carrying over all doses to the end of the trial or dropping the losers earlier. However, all the doses have to be explored. For unimodal (including linear or umbrella) response curves, we proposed an effective dose-finding design that allows adding arms at the interim analysis. The trial design starts with two arms, depending on the response of the two arms and the unimodality assumption; we can decide which new arms to be added. This design does not require exploring all arms (doses) to find the best responsive dose; therefore, it can further reduce the sample size from the drop-loser design by as much as 10-20%.

An Adaptive Staggered Dose Design for a Normal Endpoint.

In a clinical trial where several doses are compared to a control, a multi-stage design that combines both the selection of the best dose and the confirmation of this selected dose is desirable. An example is the two-stage drop-the-losers or pick-the-winner design, where inferior doses are dropped after interim analysis. Selection of target dose(s) can be based on ranking of observed effects, hypothesis testing with adjustment for multiplicity, or other criteria at interim stages. A number of methods have been proposed and have made significant gains in trial efficiency. However, many of these designs started off with all doses with equal allocation and did not consider prioritizing the doses using existing dose-response information. We propose an adaptive staggered dose procedure that allows explicit prioritization of doses and applies error spending scheme that favors doses with assumed better responses. This design starts off with only a subset of the doses and adaptively adds new doses depending on interim results. Using simulation, we have shown that this design performs better in terms of increased statistical power than the drop-the-losers design given strong prior information of dose response.

Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions.

The treatment of metastatic renal cell carcinoma (mRCC) has evolved markedly over the past decade, broaden- ing beyond immune-based strategies (eg, interleukin-2 and interferon-α) to include targeted agents (eg, sunitinib [Sutent, Pfizer] and sorafenib [Nexavar, Bayer]). Recently, there has been a renewed interest in immune-based strategies, with clinical trials underway to assess vaccines and other immunomodulatory agents. Of particular interest are agents that inhibit the interaction between the programmed death-1 (PD-1) receptor and its ligand (PD-L1) at the T-cell/antigen-presenting cell interface. This interaction produces T-cell anergy and therefore stifles the antitumor immune response. Monoclonal antibodies to PD-1 (eg, nivolumab, lambrolizumab, and pidilizumab) and PD-L1 (MPDL3280A and BMS-936559) are in various stages of clinical development. The clinical trajectory of these agents is discussed herein, with specific attention to the potential placement of PD-1/ PD-L1 inhibition in the crowded therapeutic landscape of mRCC.