Colorectal Adenocarcinoma, Head and Neck Cancer, Metastatic Solid Tumor, Recurrent Solid Tumor, Solid Tumor, Adult, Squamous Cell Carcinoma of Head and Neck
Conditions
Keywords
NT219, ERBITUX, Cetuximab
Brief summary
This is a phase 1/2, multi-center study with an open-label, dose escalation phase followed by a single-arm expansion phase to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 alone and in combination with ERBITUX® (cetuximab) in adults with recurrent and/or metastatic solid tumors.
Interventions
DRUGNT219
Dose escalation of NT219 as a single agent in adult subjects with recurrent and/or metastatic solid tumors
DRUGNT219 and ERBITUX® - Dose Escalation
Dose escalation of NT219 in combination with standard dose ERBITUX® in adult subjects with recurrent and/or metastatic squamous cell carcinoma of the head and neck and colorectal adenocarcinoma
DRUGNT219 and ERBITUX® - Expansion
Expansion cohort of NT219 at its RP2D in combination with standard dose ERBITUX® in adult patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck
Sponsors
TyrNovo Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Incidence of treatment emergent adverse events | Up to 24 months | Incidence of treatment emergent adverse events with single agent NT219 |
| Part 2: Incidence of treatment emergent adverse events | Up to 24 months | Incidence of treatment emergent adverse events with NT219 administered in combination with ERBITUX® |
| Part 3: Objective Response Rate | Up to 24 months | Objective Response Rate when phase 2 dose of NT219 is used in combination with ERBITUX® in adults with recurrent and/or metastatic SCCHN |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma half-life [t1/2] | Up to 45 days after first study drug administration | Plasma half-life \[t1/2\] of NT219 |
| Plasma clearance [Cl] | Up to 45 days after first study drug administration | Plasma clearance \[Cl\] of NT219 |
| Objective Response Rate when NT219 is used as monotherapy | Up to 24 months | — |
| Duration of Response when NT219 is used as monotherapy | Up to 24 months | — |
| Time to Response when NT219 is used as monotherapy | Up to 24 months | — |
| Disease Control Rate when NT219 is used as monotherapy | Up to 24 months | — |
| Progression Free Survival when NT219 is used as monotherapy | Up to 24 months | — |
| Time to Progression when NT219 is used as monotherapy | Up to 24 months | — |
| Area under the plasma concentration curve [AUC] | Up to 45 days after first study drug administration | Area under the plasma concentration curve \[AUC\] of NT219 |
| Objective Response Rate when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Duration of Response when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Time to Response when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Disease Control Rate when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Progression Free Survival when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Time to Progression when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Overall Survival when NT219 is used in combination with ERBITUX® | Up to 24 months | — |
| Overall Survival when NT219 is used as monotherapy | Up to 24 months | — |
| Maximum plasma concentration [Cmax] | Up to 45 days after first study drug administration | Maximum plasma concentration \[Cmax\] of NT219 |
| Volume of distribution at stead-state [Vss] | Up to 45 days after first study drug administration | Volume of distribution at stead-state \[Vss\] of NT219 |
Countries
Israel, United States
Outcome results
None listed