| Eligibility |
Portion #2: Dose escalation of NT219 in combination with ERBITUX® in adult subjects with
recurrent and/or metastatic squamous cell carcinoma head and neck and colorectal
adenocarcinoma Inclusion Criteria
1. Subject with previously treated colorectal or head and neck cancer with documentation
of incurable locally advanced, recurrent and/or metastatic squamous cell carcinoma of
the head and neck or colorectal adenocarcinoma, stage III/IV that must have failed or
not be a candidate for available standard of care therapies and not deemed amenable to
local therapy with curative intent (surgery or radiation therapy with or without
chemotherapy) by a multidisciplinary committee to include an oncologist, surgeon, and
radiation oncologist
2. Subjects with head and neck cancer should have received up to 2 previous regimens for
recurrent/metastatic disease; Only subjects with documented wild-type KRAS and BRAF
colorectal cancer are allowed to enroll; subjects with colorectal cancer should have
received up to 3 previous regimens for metastatic disease.
3. Subjects with HPV negative status only to be enrolled (for subjects with head and neck
cancer)
4. Completion of curative radiation therapy at least 4 weeks prior to study treatment
initiation; For subjects with head and neck cancer - prior focal palliative
radiotherapy must be completed at least 2 weeks prior to study drug administration
5. Availability of archival tumor samples prior to treatment initiation; When not
available or feasible for any reason, this requirement can be waived after discussion
with the Sponsor.
6. Fresh tumor biopsy should be obtained unless deemed by the investigator that the
procedure may pose a risk of bleeding to the subject or otherwise deemed not medically
safe and/or feasible for any reason. This biopsy must be either formalin-fixed,
paraffin-embedded (FFPE) tissue block or unstained tumor tissue samples, obtained
within 3 months prior to enrollment and after the last systemic treatment was
completed, with an associated pathology report. Biopsy should be excisional,
incisional or core needle. Fine needle aspiration biopsy of the involved neck lymph
nodes is permitted however, fine needle aspiration or biopsies of bone lesions that do
not have a soft tissue component are unacceptable for submission.
7. Must have at least 1 measurable lesion per RECIST1.1 with progressing or new lesions
since last antitumor therapy.
8. Age =18 years at the time of signing ICF;
9. ECOG performance status score of <2 at Screening and Baseline (Day 0);
10. Adequate safety lab results at Screening and at Baseline (Day 0) for those tests that
require repeating at Baseline, including the following:
1. Albumin =3 g/dL
2. Bilirubin =1.5 times the upper limit of normal (ULN) or <3 times the ULN in the
case of Gilbert Syndrome
3. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), and alkaline
phosphatase <3 times the ULN
4. Creatinine clearance >60 mL/minute based on the Cockcroft-Gault equation
[creatinine clearance in mL/min = (140 - age in years) x body weight (kg)/72 x
serum creatinine (mg/dL); multiplied by 0.85 for women]
5. White blood cell (WBC) count =2000/uL; hemoglobin =9 g/dL;
11. Brain metastases should be stable following radiosurgery with at least 4 weeks since
the end of definitive therapy (i.e., radiotherapy)
12. Subjects must have a "wash out" period of at least 4 weeks prior to first study drug
administration from all previous chemotherapy and/or experimental agents except for
anti-PD-1 antibodies which must have a "wash out" period of at least 6 weeks prior to
first study drug administration, and all adverse events (AEs) have either returned to
baseline or stabilized at Grade 1 or less.
13. Subject can understand and sign the ICF, can communicate with the PI, and can
understand and comply with the requirements of the protocol;
14. WCBP must have a negative serum pregnancy test at Screening and a negative urine
pregnancy test at Baseline (Day 0)
15. WCBP must agree to abstain from sex or use an adequate method of contraception* from
the time of informed consent through 2 months after the last dose of NT219;
16. Males must abstain from sex with WCBP or use an adequate method of contraception* from
the time of informed consent through 2 months after the last dose of study drug.
- Adequate contraceptive methods include those with a low failure rate, i.e., less
than 1% per year, when used consistently and correctly, such as some double
barrier methods (condom with spermicide) in conjunction with use by the partner
of an intrauterine device, diaphragm with spermicide, oral contraceptives, birth
control patch or vaginal ring, or injectable or implanted contraceptives.
Abstinence is acceptable only as true abstinence: when this is in line with the
preferred and usual lifestyle of the subject. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
A woman that is postmenopausal (=2 years since last menstrual period) or permanently
sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy) is not considered
a WCBP.
Portion #3: Expansion cohort of NT219 in combination with ERBITUX® in adult subjects with
recurrent and/or metastatic squamous cell carcinoma head and neck Inclusion Criteria
1. Subject with previously treated head and neck cancer, with documentation of incurable
locally advanced, recurrent and/or metastatic squamous cell carcinoma of the head and
neck, stage III/IV and not deemed amenable to local therapy with curative intent
(surgery or radiation therapy with or without chemotherapy) by a multidisciplinary
committee to include an oncologist, surgeon, and radiation oncologist
2. Patient has received up to 2 previous regimens for recurrent/metastatic disease;
3. Subjects with HPV negative status only to be enrolled Completion of curative radiation
therapy at least 4 weeks prior to study treatment initiation; prior focal palliative
radiotherapy must be completed at least 2 weeks prior to study drug administration
4. Availability of archival tumor samples prior to treatment initiation; When not
available or feasible for any reason, this requirement can be waived after discussion
with the Sponsor.
5. Fresh tumor biopsy should be obtained unless deemed by the investigator that the
procedure may pose a risk of bleeding to the subject or otherwise deemed not medically
safe and/or feasible for any reason. This biopsy must be either formalin-fixed,
paraffin-embedded (FFPE) tissue block or unstained tumor tissue samples, obtained
within 3 months prior to enrollment and after the last systemic treatment was
completed, with an associated pathology report. Biopsy should be excisional,
incisional or core needle. Fine needle aspiration biopsy of the involved neck lymph
nodes is permitted however, fine needle aspiration or biopsies of bone lesions that do
not have a soft tissue component are unacceptable for submission.
6. Must have at least 1 measurable lesion per RECIST1.1 with progressing or new lesions
since last antitumor therapy.
7. Age =18 years at the time of signing ICF;
8. ECOG performance status score of <2 at Screening and Baseline (Day 0);
9. Adequate safety lab results at Screening and at Baseline (Day 0) for those tests that
require repeating at Baseline, including the following:
1. Albumin =3 g/dL
2. Bilirubin =1.5 times the upper limit of normal (ULN) or <3 times the ULN in the
case of Gilbert Syndrome
3. Aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), and alkaline
phosphatase <3 times the ULN
4. Creatinine clearance >60 mL/minute based on the Cockcroft-Gault equation
[creatinine clearance in mL/min = (140 - age in years) x body weight (kg)/72 x
serum creatinine (mg/dL); multiplied by 0.85 for women]
5. White blood cell (WBC) count =2000/uL; hemoglobin =9 g/dL
10. Brain metastases should be stable following radiosurgery with at least 4 weeks since
the end of definitive therapy (i.e., radiotherapy)
11. Subjects must have a "wash out" period of at least 4 weeks prior to first study drug
administration from all previous chemotherapy and/or experimental agents except for
anti-PD-1 antibodies which must have a "wash out" period of at least 6 weeks prior to
first study drug administration, and all adverse events (AEs) have either returned to
baseline or stabilized at Grade 1 or less.
12. Subject can understand and sign the ICF, can communicate with the PI, and can
understand and comply with the requirements of the protocol
13. WCBP must have a negative serum pregnancy test at Screening and a negative urine
pregnancy test at Baseline (Day 0)
14. WCBP must agree to abstain from sex or use an adequate method of contraception* from
the time of informed consent through 2 months after the last dose of NT219;
15. Males must abstain from sex with WCBP or use an adequate method of contraception* from
the time of informed consent through 2 months after the last dose of study drug.
- Adequate contraceptive methods include those with a low failure rate, i.e., less
than 1% per year, when used consistently and correctly, such as some double
barrier methods (condom with spermicide) in conjunction with use by the partner
of an intrauterine device, diaphragm with spermicide, oral contraceptives, birth
control patch or vaginal ring, or injectable or implanted contraceptives.
Abstinence is acceptable only as true abstinence: when this is in line with the
preferred and usual lifestyle of the subject. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
A woman that is postmenopausal (=2 years since last menstrual period) or permanently
sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy) is not considered
a WCBP.
Exclusion Criteria for Study Portions #2 & #3:
The exclusion criteria for Study Portion #2 drug combination dose escalation and Study
Portion#3, the expansion phases of the trial are identical. Subjects meeting any of the
following exclusion criteria will not be enrolled in the trial:
1. Nasal, paranasal sinus, or nasopharyngeal carcinoma and mutated KRAS colorectal
adenocarcinoma, aside from World Health Organization (WHO) Type I and II
[keratinizing, non-Epstein-Barr virus (EBV) positive] nasopharyngeal carcinoma which
will be allowed;
2. In Study Part 2: For subjects with HNSCC: Received more than 2 prior systemic regimens
for their HNSCC; For subjects with CRC: Received more than 3 prior systemic regimens
for their CRC; In Study Part 3: For subjects with HNSCC: Received more than 2 prior
regimens for their recurrent/metastatic HNSCC
3. Received cetuximab as part of the most recent regimen and/or within the last 6 months
prior to study registration
4. Any invasive cancer (other than non-melanoma skin cancer) different from the current
disease within 3 years of Screening
5. Known hypersensitivity to ERBITUX® or other epidermal growth factor receptor (EGFR),
Janus kinase (JAK), or signal transducer and activator of transcription (STAT)
antagonists/inhibitors, or inactive ingredients of NT219 Injection.
6. Radiation or major surgery within 4 weeks prior to the first dose of NT219;
7. Treatment with another investigational therapy within 30 days or 5 half-lives of the
drug prior to Screening, whichever is longer
8. Parenteral vitamin C administration and oral supplements containing vitamin C
9. History of weight loss >10% over the 2 months prior to Screening
10. Active, untreated central nervous system (CNS) metastases
11. Severely immunocompromised as defined by white blood cell (WBC) count <2000/mm3 and/or
CD4+ lymphocyte count =200/mm3
12. Major surgery within 4 weeks of study administration;
13. Known allergy to tick bites or red meat, or known immunoglobulin E (IgE) antibodies
directed against galactose-a-1,3-galactose
14. Any condition which, in the opinion of the PI, places the subject at unacceptable risk
if he/she were to participate in the study
15. Clinically relevant serious co-morbid medical conditions including, but not limited
to:
1. Active infection
2. History of long QT syndrome or corrected QT interval (QTc) or QT/QTc interval
measured as prolonged at screening (>480 ms; using Fredericia's QT correction
formula). Note: subjects who screen fail due to this criterion are not eligible
to be re-screened;
3. A history of additional risk factors for TdP including clinically significant
prolonged electrolytes imbalance, left ventricular dysfunction and left
ventricular hypertrophy, prolonged diarrhea, bradycardia < 60 bpm, past history
of syncope or a family history of sudden death at age <40 years
4. The use of concomitant medications that prolong the QT/QTc interval or
experienced arrhythmias with use of agents known to induce TdP.
5. Recent (within six months of Screening) New York Heart Association (NYHA) Class
III or IV cardiac disease, myocardial infarction, or severe or unstable angina;
6. History of serious arrhythmia (i.e., ventricular tachycardia or ventricular
fibrillation) or cardiac arrhythmias requiring anti-arrhythmic medications
7. Global Initiative for Chronic Obstructive Lung Disease (GOLD) score =3 chronic
obstructive or chronic restrictive pulmonary disease, pulmonary hypertension, or
interstitial pneumonitis
8. Active CNS disease including carcinomatous meningitis;
9. Psychiatric illness/social situation that would limit compliance with study
requirements; Prior organ allograft
10. Subjects with active, known or suspected autoimmune disease. Subjects with the
following are permitted to enroll: (subjects with vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune condition only requiring
hormone replacement, euthyroid patients with a history of Grave's disease
(subjects with suspected autoimmune thyroid disorders must be negative for
thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating
immunoglobulin prior to first dose of study drug), psoriasis not requiring
systemic treatment, or conditions not expected to recur in the absence of an
external trigger.
11. Subjects with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration except for adrenal
replacement steroid doses >10 mg daily prednisone equivalent in the absence of
active autoimmune disease. Note: Treatment with a short course of steroids (< 5
days) up to 7 days prior to initiating study drug is permitted.
12. History of active or latent tuberculosis infection
13. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus
(HBV), or hepatitis C virus (HCV) as follows:
Subjects with HIV: detectable viral load and CD4 count below 200 cells/mm3; Subjects
with HBV (HepBsAg+): serum HBV DNA polymerase chain reaction (PCR) that is above the
limit of detection Subjects with HCV (Ab +): detectable HCV RNA by PCR
16. Pregnant or lactating women
17. Use of UGT inhibitors within 14 days prior to first dose of study treatment. Morphine
and similar agents and statins which are commonly used in oncology subjects are
permitted. See Appendix E for sample list of prohibited UGT inhibitors.
|
