Bempegaldesleukin (NKTR-214) With Radiation and Anti-PD-1 Immunotherapy for Head and Neck Squamous Cell Carcinoma

Phase 2

Terminated

Conditions: Head and Neck Cancer

Interventions: Drug: NKTR-214
Drug: anti-PD-1 therapy
Radiation: Palliative Radiation

Registration Number: NCT04936841

Lead Sponsor: University of Wisconsin, Madison

Brief Summary: This trial will evaluate safety and efficacy of the combination of anti-PD1, NKTR-214, and palliative radiation therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Twenty-four participants will be enrolled to evaluate the efficacy of this combination.

Detailed Description: Following an informed consent process, participants will receive anti-PD-1 therapy with 200 mg of pembrolizumab and NKTR-214 at 0.006 mg/kg. Palliative radiation therapy will then be delivered to tumor sites causing or felt by the treating physician to have a high potential for causing symptoms with either 8 Gy X 3 or 4 Gy X 5 completed 3 to 7 days prior to cycle 2 of anti-PD1 and NKTR-214. Combined anti-PD-1 and NKTR-214 will then be delivered each subsequent cycle.

Efficacy will be measured by overall response rate (ORR), progression free survival (PFS), overall survival (OS), clinical benefit (CB), and duration of response with ORR the primary outcome being compared to historical control data. Toxicity will be evaluated prior to administration of each 21-day cycle, while receiving NKTR-214 followed by every four months after the participant is off trial. Health related quality of life questionnaires will be completed with cycle 1 and 2 and then every 4 cycles thereafter.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
Qualify for anti-PD-1 therapy based on current guidelines at the time of registration. This includes the standard requirement for the participant's tumor to have been previously determined to express PD-L1 with a combined positive score ≥ 1, as determined by an FDA-approved test.
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 within 30 days prior to enrollment
Histologically proven diagnosis of head and neck squamous cell carcinoma that is metastatic or recurrent disease that is surgically incurable
Prior cancer treatment other than anti-PD-1 therapy must be completed at least 30 days prior to registration and the participant must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. Participants may not undergo concurrent anti-cancer treatment during treatment with protocol therapies. This includes no treatment with growth factors, tyrosine kinase inhibitors, tumor-specific antibodies, or cytotoxic chemotherapies such as cisplatin. Participants who have previously or are currently taking an anti-PD-1 therapy are eligible for this study if they meet eligibility criteria 2. Participants who have previously taken any other immune checkpoint inhibitor are eligible as long as they have completed that treatment at least 30 days prior to registration and meet all other eligibility criteria.
Participants with central nervous system (CNS) metastases are eligible if the CNS lesions are stable for at least 2 months and if tapered off treatment doses of systemic corticosteroids for at least 2 weeks prior to enrollment on the trial. Management with maintenance physiologic doses of corticosteroids (equivalent doses of prednisone ≤ 10 mg daily) is acceptable.
Participants must have an "index" tumor that: 1) is deemed by the treating radiation oncologist to potentially benefit from palliative radiation 2) is amenable to biopsy, 3) is ≥ 1 cm in longest dimension.
Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 30 days prior to enrollment
- White blood cell (WBC) ≥ 3,000/mm3
- Absolute Neutrophil Count (ANC) ≥ 1,500/mm3
- Hemoglobin (Hgb) ≥ 9 g/dL
- Platelets ≥ 100,000/mm3
- Serum creatinine ≤ 2.0 mg/dL
- Total Bilirubin ≤ 2.0 × upper limit of normal (ULN) (< 3.0 for subjects with Gilbert's Syndrome)
- Aspartate aminotransferase (AST) ≤ 3 × ULN
- Alanine aminotransferase (ALT) ≤ 3 × ULN
Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to enrollment and must agree to use effective contraception during active treatment and for 5 months after last dose of pembrolizumab and/or NKTR-214. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for ≥ 12 consecutive months.
As determined by the enrolling physician or protocol designee, ability of the participant to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

Subjects with significant intercurrent illnesses per physician discretion
Subjects with active or acute infections or active peptic ulcers, unless these conditions are adequately corrected or controlled, in the opinion of the treating physician
Subjects with a diagnosed auto-immune disease (exceptions: subjects with controlled diabetes mellitus type I, thyroid disease, rheumatoid arthritis, vitiligo and alopecia areata not requiring treatment with immunosuppressants are eligible)
- Subjects with a history of diabetes mellitus requiring systemic therapy within the past 3 months (i.e. either oral hypoglycemic agents or insulin) must have a documented Hemoglobin A1c < 8.0 % within 90 days of registration.
Subjects with known genetic conditions causing pre-disposition to radiotherapy (RT) toxicity (i.e.: Li-Fraumeni, ATM deficiency, active scleroderma, etc.)
Participants with a prior diagnosis of cerebrovascular accident (CVA) or transient ischemic attack (TIA)
Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three years prior to enrollment
Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at time of enrollment
Subjects with symptoms of ischemic cardiac disease, congestive heart failure, or myocardial infarction within 6 months of registration and/or uncontrolled cardiac rhythm disturbance
Subjects with a pulmonary embolism, deep vein thrombosis, or prior clinically significant venous or non-CVA/TIA arterial thromboembolic event (e.g., internal jugular vein thrombosis) within 3 months prior to enrollment
- Patients with a history of a venous or arterial thromboembolic event must be asymptomatic prior to enrollment and must be receiving a stable regimen of therapeutic anticoagulation (low molecular weight heparin (LMWH) or direct oral anticoagulation (DOAC)). Use of coumadin is permitted; however, therapeutic dosing should target a specific international normalized ratio (INR) stable for at least 4 weeks prior to enrollment. NKTR-214 has the potential to down-regulate metabolizing enzymes for coumadin for approximately 1 week after administration of each dose of NKTR-214. Due to the possibility of drug-drug interactions between coumadin and NKTR-214, frequent monitoring of INR and ongoing consideration of dose adjustments are warranted throughout the patient's participation on study.
Subjects with significant psychiatric disabilities or seizure disorders if considered unsafe in the opinion of the treating physician
Subjects with symptomatic pleural effusions or ascites
Subjects with organ allografts
Subjects who require, or are likely to require, systemic treatment doses of corticosteroids, or other immunosuppressive drugs, or have used them within 2 weeks of registration (clarification: subjects receiving physiologic maintenance or replacement doses of systemic steroids or inhaled steroids are eligible)
Subjects with known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C infection, or with clinical evidence of hepatitis 15. Subjects with known hypersensitivity to IL2 or those who experienced significant immune-related AEs requiring treatment with steroids or other immunosuppressant therapy during prior treatment with ipilimumab, or anti- PD-1/PD-L1 checkpoint blockade therapy 16. Subjects who cannot provide independent, legal, informed consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NKTR-214, anti-PD therapy plus Palliative Radiation	anti-PD-1 therapy	Cycle 1 consists of anti-PD-1 therapy (200mg) and NKTR-214 (0.006 mg/kg3 administered intravenously), followed by palliative radiation (8 Gy x 3 or 4 Gy x 5 fractions) combined with anti-PD-1 therapy and NKTR-214 in cycle 2. In subsequent cycles participants will receive NKTR-214 and anti-PD-1.
NKTR-214, anti-PD therapy plus Palliative Radiation	Palliative Radiation	Cycle 1 consists of anti-PD-1 therapy (200mg) and NKTR-214 (0.006 mg/kg3 administered intravenously), followed by palliative radiation (8 Gy x 3 or 4 Gy x 5 fractions) combined with anti-PD-1 therapy and NKTR-214 in cycle 2. In subsequent cycles participants will receive NKTR-214 and anti-PD-1.
NKTR-214, anti-PD therapy plus Palliative Radiation	NKTR-214	Cycle 1 consists of anti-PD-1 therapy (200mg) and NKTR-214 (0.006 mg/kg3 administered intravenously), followed by palliative radiation (8 Gy x 3 or 4 Gy x 5 fractions) combined with anti-PD-1 therapy and NKTR-214 in cycle 2. In subsequent cycles participants will receive NKTR-214 and anti-PD-1.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	up to 7 months (at Standard-of-care imaging 3 to 6 months after Cycle 1)	ORR is the percentage of participants whose cancer shrinks or disappears after treatment. ORR will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST1.1, by investigator assessment.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events Greater Than or Equal to Grade 3	up to 14 months (study terminated early)	Toxicities ≥ Grade 3 is defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities not "unrelated" to treatment, will be considered treatment-related. Adverse events are evaluated by the physician graded from 1-5 where 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = death.
Health Related Quality of Life as Measured by EORTC QLQ-C30: Global and Functional Sub-Scores	Baseline at screening, cycle (C)1 day (D)8 (about 2 weeks on study), C2D8 (about 5 weeks on study), C3D8 (about 8 weeks on study), 30-day post (about 12 weeks on study)	European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) is a measure of health-related quality of life for cancer patients participating in clinical trials. It scores the following domains from 0-100 where higher global or functional scores indicate increased quality of life and higher symptom scores indicate increased symptoms: Global health status (QL2), Physical functioning (PF2), Role functioning (RF2), Emotional functioning (EF), Cognitive functioning (CF), and Social functioning (SF).
Health Related Quality of Life as Measured by EORTC QLQ-H&N35 Sub-Scores	Baseline at screening, cycle (C)1 day (D)8 (about 2 weeks on study), C2D8 (about 5 weeks on study), C3D8 (about 8 weeks on study), 30-day post (about 12 weeks on study)	European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire - Head and Neck (EORTC QLQ-H\&N35) is comprised of the following subscales, scored from 0-100 where higher scores indicate increased symptoms: Pain (HNPA), Swallowing (HNSW), Senses problem (HNSE), Speech problems (HNSP), Trouble with social eating (HNSO), Trouble with social contact (HNSC), Less sexuality (HNSX), Teeth (HNTE), Opening mouth (HNOM), Dry mouth (HNDR), Sticky saliva (HNSS), Coughing (HNCO), Felt ill (HNFI), pain killers (HNPK), Nutritional supplements (HNNU), Feeding tube (HNFE), Weight loss (HNFL), Weight gain (HNWG)
Health Related Quality of Life as Measured by EORTC QLQ-C30: Symptom Sub-Scores	Baseline at screening, cycle (C)1 day (D)8 (about 2 weeks on study), C2D8 (about 5 weeks on study), C3D8 (about 8 weeks on study), 30-day post (about 12 weeks on study)	European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) is a measure of health-related quality of life for cancer patients participating in clinical trials. It scores the following domains from 0-100 where higher symptom scores indicate increased symptoms: Fatigue (FA), Nausea and vomiting (NV), Pain (PA), Dyspnea (DY), Insomnia (SL), Appetite loss (AP), Constipation (CO), Diarrhea (DI), Financial difficulties (FI)
Summary of Adverse Events Greater Than or Equal to Grade 3 by Count of Participants Who Experienced Them	up to 14 months (study terminated early)	Toxicities ≥ Grade 3 is defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities not "unrelated" to treatment, will be considered treatment-related. Adverse events are evaluated by the physician and graded from 1-5 where 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, and 5 = death.
Overall Survival (OS)	up to 14 months (study terminated early)	OS is defined as time from day 1 of treatment until death as a result of any cause.
Duration of Response	up to 14 months (study terminated early)	Duration of response is the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented.
Health Related Quality of Life as Measured by EQ-5D Participant Counts	Baseline at screening, cycle (C)1 day (D)8 (about 2 weeks on study), C2D8 (about 5 weeks on study), C3D8 (about 8 weeks on study), 30-day post (about 12 weeks on study)	The EQ-5D is a 5 question measure of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus an overall measure of health reported on a visual analog scale. Participant counts are reported for each of 5 dimensions: mobility, self-care, usual activities, pain / discomfort, anxiety / depression.
Progression Free Survival (PFS)	up to 14 months (study terminated early)	PFS is the average length of time after the start of treatment in which a person is alive, and their cancer does not grow or spread. PFS is defined as the time from day 1 of treatment until the criteria for disease progression is met as defined by RECIST1.1 or death as a result of any cause.
Number of Participants With Clinical Benefit (CB)	up to 14 months (study terminated early)	CB will include confirmed complete response (CR) + confirmed partial response (PR) + stable disease at ≥ 6 months (SD) and will be determined as per RECIST1.1.