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.
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.
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
