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Pembrolizumab

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Subjects will receive IV infusions of tabelecleucel at 2 × 10\^6 T-cells/kg on Days 1, 8, and 15; and an IV infusion of pembrolizumab at 200 mg for adults or 2 mg/kg for adolescents on Day 1 of each 21-day cycle (at least 2 cycles or up to 4 cycles). For Cohort 1, if there is a dose-limiting toxicity, the dose of tabelecleucel will be reduced to 1 x 10\^6 cells/kg and pembrolizumab will continue to be administered as above. Otherwise, all subjects in Cohort 1 will receive tabelecleucel at 2 x 10\^6 cells/kg/dose and pembrolizumab as above. Subjects in Cohort 2 will receive the recommended Phase 2 dose of tabelecleucel per the SDRC and pembrolizumab as above.

Tabelecleucel is an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.

tabelecleucel

pembrolizumab

Willis Navarro, MD

This is a multicenter, open-label, single-arm Phase 1B/2 study to assess the safety and efficacy of tabelecleucel in combination with pembrolizumab for the treatment of subjects with platinum-pretreated, recurrent/metastatic Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC).

This is a multicenter, open-label, single-arm Phase 1B/2 study to assess the safety and efficacy of tabelecleucel in combination with pembrolizumab for the treatment of subjects with platinum-pretreated, recurrent/metastatic EBV+ NPC.

Tabelecleucel will be selected for each subject from the bank of available tabelecleucel cell products based on matching ≥ 2 human leukocyte antigen (HLA) alleles, at least one of which is a restricting HLA allele, shared between the tabelecleucel donor and the subject's EBV+ NPC. Sites will provide high resolution HLA typing of the subject and other information as required by the protocol.

Phase 1B will identify the maximum tolerated dose (MTD) and characterize the dose limiting toxicity (DLT) for tabelecleucel in combination with pembrolizumab in up to 24 subjects. In the absence of an MTD, the recommended Phase 2 dose (RP2D) will be identified. Phase 2 will evaluate the safety and efficacy of the combination in 36 subjects at the recommended dose level from Phase 1B.

Tabelecleucel in Combination With Pembrolizumab in Subjects With Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC)

An Open-Label Phase 1B/2 Study to Evaluate the Safety and Efficacy of Tabelecleucel in Combination With Pembrolizumab in Subjects With Platinum-pretreated, Recurrent/Metastatic Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma

The ORR is defined as complete response (CR) or partial response (PR) confirmed \>= 28 days from the initial response assessment showing a response.

Merck Sharp & Dohme LLC

Atara Biotherapeutics

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Carcinoma, Squamous Cell

Papillomavirus Infections

Papilloma

Oropharyngeal Neoplasms

Carboplatin

Cisplatin

Low risk patients are defined as T1-T2 AND 0 or 1 metastatic lymph nodes AND \<3 cm AND clear (≥3mm) margins AND no extracapsular extension (ECE) AND no perineural invasion AND no lymphovascular invasion.

Patients will undergo transoral surgical resection of the oropharyngeal tumor.

Intermediate risk patients are defined as having any of the following features: One or more close (\<3mm) margins, OR "minimal" ≤1 mm ECE OR 1 or more metastatic lymph nodes \>3 cm in diameter OR 2-4 lymph nodes positive (≤ 6 cm in diameter), OR perineural invasion OR lymphovascular invasion

Patients will undergo transoral surgical resection of the oropharyngeal tumor. Following surgery, patients will receive low-dose IMRT five times a week for 3 weeks.

High risk patients are defined as having any of the following features: One or more positive margins OR \>1 mm ECE OR ≥ 5 metastatic lymph nodes.

Patients will undergo transoral surgical resection of the oropharyngeal tumor. Following surgery, patients will receive low-dose IMRT six times a week and a weekly chemotherapy infusion (cisplatin or carboplatin) during radiation therapy.

Patients will receive 2 Gy/fraction, 6 fractions per week with at least a 6-hour interfraction interval between each treatment:

* PTV-P50 or PTV-N50: 50 Gy in 25 fractions (2 Gy/fx)
* PTV-N45: 45 Gy in 25 fractions (1.8 Gy/fx) with simultaneous integrated boost to the PTV-P50 volume.
* PTV-P30 or PTV-N30: 30 Gy in 15 fractions (2 Gy/fx)

Transoral surgical resection of tumor(s).

therapeutic conventional surgery

laboratory biomarker analysis

quality-of-life assessment

intensity-modulated radiation therapy

Brieana Marino, MS

Samantha Demko, RN, BSN

Heath D Skinner, MD, PhD

Umamaheswar Duvvuri, MD, PhD

Dan Zandberg, MD

Simon Chiosea, MD

Robert L Ferris, MD, PhD

Heath Skinner, MD, PhD

This is a trial studying patients with human papilloma virus (HPV) positive oropharyngeal cancer with tumors that can be removed via transoral surgery. Following surgery, patients will be classified as either low, intermediate, or high risk based on the characteristics of the tumors. Low risk patients (Arm S) will receive no further treatment after surgery. Intermediate risk patients (Arm RT) will be treated with Intensity Modulated Radiotherapy (IMRT) after surgery. High risk patients (Arm CRT) will receive a combination of IMRT and chemotherapy after surgery. Patients will be followed for up to five years after the completion of treatment.

This phase II trial is designed to rationally de-escalate adjuvant (Intensity Modulated Radiotherapy (IMRT) in the post-transoral surgery (TOS) setting in a study population consisting of patients with resectable oropharynx carcinoma, p16+ as confirmed by immunohistochemistry IHC, with a performance status (PS) of 0-1. Patients will be classified into one of three category/treatment groups (low-, intermediate-, and high-risk) according to their highest pathologically risk feature. Radiation will be given via an IMRT technique. For the high-risk patient group, a reduced, but slightly accelerated radiotherapy (RT) fractionation regimen of 50 Gy (HCC 18-034) in conjunction with cisplatin will be used compared to the standard 66 Gy and cisplatin. Low risk patients will transition to observation, intermediate risk patients will receive 30 Gy in 15 fractions of IMRT, and high risk patients will receive 50 Gy in 25 fractions (one day a week will include two treatments) plus 40 mg/m2 Cisplatin for 5 weeks. Patients who are not able to tolerate cisplatin will receive carboplatin instead.

Transoral Surgical Resection Followed by De-escalated Adjuvant IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer

Phase II Trial of Transoral Surgical Resection Followed by De-escalated Adjuvant IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer

Time to recurrence, defined as local and/or regional progression (identification of disease growth that is present within the area in which it was first located) and/or distant metastasis (identification of disease growth that is present in area(s) distant to that previously located). Local progression is defined as progression at the primary tumor site. Regional progression is defined as progression in the draining lymphatics (typically the cervical, retropharyngeal/retrostyloid and supraclavicular lymph nodes). Distant progression is defined as tumor recurrence in one or more non-local and non-regional sites (e.g., bone, lung, liver, etc.). Recurrent malignancy will be determined based on clinical exam and imaging findings. Patients who are disease-free but who die from other causes will be censored.

Loco-regional control will be evaluated based on the percentage of patients without recurrence (identification of disease growth) in the primary site or regional lymphatics based on imaging and/or clinical exam.

Percentage of patients with distant metastasis (identification of disease growth that is present in area(s) distant to that previously located) evident on imaging and/or clinical exam. Distant metastasis is defined as tumor recurrence in one or more non-local (at the primary tumor) and non-regional (draining lymphatic) sites such as bone, lung, liver, etc.

Overall survival will be measured as the time from start of treatment to death from any cause.

The percentage of total patients enrolled in the study allocated to low (Arm S), intermediate (Arm RT) and high risk (Arm CRT) groups. Histologic risk features are defined as follows: Low risk (ARM S) - T1-T2 AND 0 or 1 metastatic lymph nodes AND \<3 cm AND clear (≥3mm) margins AND no extracapsular extension (ECE) AND no perineural invasion AND no lymphovascular invasion; Intermediate risk (ARM RT) - Any of the following features: One or more close (\<3mm) margins, OR "minimal" ≤1 mm ECE OR 1 or more metastatic lymph nodes \>3 cm in diameter OR 2-4 lymph nodes positive (≤ 6 cm in diameter), OR perineural invasion OR lymphovascular invasion; High risk (ARM CRT) - Any of the following features: One or more positive margins OR \>1 mm ECE OR ≥ 5 metastatic lymph nodes.

The percentage of patients that have a feeding tube, by Arm, for the low (Arm S), intermediate (Arm RT) and high risk (Arm CRT) groups following treatment with transoral resection and adjuvant therapy.

Number of patients experiencing toxicities related to study treatment per Common Terminology Criteria for Adverse Events (CTCAE v5.0) determined at each follow-up summarized by frequency and grade.

FACT-HN is a self-administered questionnaire. Item responses are on a Likert scale score ranging from 0 to 4. Individual responses are summed to compute subscale scores, and the subscales to compute overall total scores. FACT-HN includes 2 parts - FACT-G and FACT-HN. The basic FACT-G (general) is comprised of 27 items, with four subscales including Physical Well-Being (score = 0-28), Social/Family Well-Being (score= 0-28), Emotional Well-Being (score = 0-24), and Functional Well-Being, (score = 0-28), for a total score min/max = 0-108. The FACT-HN is comprised of 12 head and neck specific items (0-48). Thus, the overall total possible score range is 0-156. Analysis will include the FACT Head \& Neck Trial Outcome Index, a composite score which includes only physical, functional, and FACT-HN, thus, scores range from 0-104. Higher scores indicate better Quality of Life.

Patient-reported swallowing perception and performance using MDASI-HN measures treatment related symptom burden in head and neck cancer patients. The 20-item MDASI measures both severity and burden of symptoms and their effect on patients' daily activities, using a numeric rating scale of 0-10. This instrument includes 13 core symptoms and 9 head and neck specific items. Higher scores indicate superior perception of function.

Three swallowing outcomes will be rated by the SLP conducting the MBS study and reported by research staff: 1) laryngeal penetration (yes, no); 2) aspiration (no, sensate, silent), and 3) pharyngeal residue (no, \< 50%, \> 50%). These have been selected as universal items generally reported by swallowing clinicians that have been shown to significantly predict pneumonia in patients with oropharyngeal cancers. Prevalence of these dysphagia endpoints will be estimated at each time point.

Patient-reported voice outcomes will be assessed using the Voice Handicap Index-10 (VHI-10) survey. The VHI-10 is a patient self-assessment instrument that quantifies patients' perception of their voice handicap. It evaluates patient's physical (P), emotional (E), and functional (F) perceptions of voice and has shown to be highly reliable for internal consistency and test-retest stability. The VHI-10 utilizes a 10-item questionnaire in which the patient circles the response that most accurately reflects his or her own experience on a linear scale (from "never" to "always"). "Always" response is scored 4 points, a "Never" response is scored 0. The remaining options are scored between 1 and 3 points. The tallied number of points for each of the subscales is computed to a total composite score. The patient's values are compared to published norms.

The Performance Status Scale (PSS-HN) is a clinician-rated instrument consisting of 3 questions: normalcy of diet, public eating/swallowing, and understandability of speech subscales in patients with head and neck cancer. Each subscale is rated from 0 to 100, with higher scores indicating better performance.

Patient-reported swallowing-related quality of life will be measured using the MD Anderson Dysphagia Inventory (MDADI). It evaluates the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. The MDADI is a 20-item questionnaire in which the patient circles the response that best reflects their experience in the past week on a 5-point Likert Scale with answers ranging from "Strongly Agree" (scored as 1 point on all questions except E7 and F2, where it is scored as 5 points) to "Strongly Disagree" (scored as 5 points on all questions except E7 and F2, where it is scored as 1 point). Scores for individual questions are summed and averaged to obtain a composite score ranging from 20 (extremely low swallow functioning) to 100 (high swallow functioning).

Heath Skinner

Assistant Professor of Medicine

Digestive System Diseases

Gastrointestinal Diseases

Stomatitis

Mucositis

Mouth Diseases

Gastroenteritis

clinical trial material; (placebo or SCV 07) at doses of 0 (placebo), 0.1, 0.3, and 1.0 mg/kg will be administered sc

SCV-07

Placebo

Israel Rios, MD

This is a phase 2b, double-blind, placebo-controlled, 4-arm, adaptive-design trial, initially stratified by cisplatin regimen, and then randomized 1:1:1:1. The study will be conducted in subjects receiving ChemoRT for the treatment of squamous cell carcinomas (SCCs) of the oral cavity, oropharynx, hypopharynx, or larynx. The study includes a treatment period of approximately 7 weeks, depending on the subject's prescribed radiation plan, and Week 1 and Week 4 post RT follow-up visits. It also includes a longer follow-up period of approximately 12 months to determine if there is an effect of SCV 07 on the tumor response to ChemoRT.

Study to Evaluate the Efficacy and Safety of Three Different Doses of SCV 07 in Attenuating Oral Mucositis in Subjects With Head and Neck Cancer

A Phase 2b, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Three Different Doses of SCV 07 in Attenuating Oral Mucositis in Subjects With Head and Neck Cancer Receiving Concurrent Chemotherapy and Radiotherapy

The primary objective of the study is to evaluate the efficacy of SCV 07 in modifying the course of oral mucositis (OM) in subjects with head and neck cancer (HNC) receiving concurrent ChemoRT.

The secondary objective of the study is to evaluate the safety and tolerability of SCV 07.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Tabelecleucel in Combination With Pembrolizumab in Subjects With Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC)	NCT03769467	Nasopharyngeal ... Nasopharyngeal ... Epstein-Barr Vi... Epstein-Barr Vi... Epstein-Barr Vi...	tabelecleucel pembrolizumab	12 Years -	Atara Biotherapeutics
Transoral Surgical Resection Followed by De-escalated Adjuvant IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer	NCT05388773	Oropharynx Canc...	therapeutic con... laboratory biom... quality-of-life... intensity-modul... Cisplatin Carboplatin	18 Years -	University of Pittsburgh
Study to Evaluate the Efficacy and Safety of Three Different Doses of SCV 07 in Attenuating Oral Mucositis in Subjects With Head and Neck Cancer	NCT01247246	Oral Mucositis	SCV-07 Placebo	18 Years -	SciClone Pharmaceuticals
Tabelecleucel in Combination With Pembrolizumab in Subjects With Epstein-Barr Virus-associated Nasopharyngeal Carcinoma (EBV+ NPC)	NCT03769467	Nasopharyngeal ... Nasopharyngeal ... Epstein-Barr Vi... Epstein-Barr Vi... Epstein-Barr Vi...	tabelecleucel pembrolizumab	12 Years -	Atara Biotherapeutics

Spots Global Cancer Trial Database for stomatognathic diseases