This is a two-part, open-label phase 1 study to evaluate safety and preliminary efficacy of M-CENK Suspension for Infusion, Cryopreserved, and N-803 for subcutaneous administration in subjects with locally advanced or metastatic solid tumors. The study consists of two cohorts: cohort 1 includes subjects with either newly diagnosed solid tumors who have not received prior therapy or subjects who have received prior first line treatment; and cohort 2 that includes subjects with relapsed/refractory (r/r) solid tumors who have progressive disease after receiving ≥ 2 prior therapies. The two cohorts will be conducted simultaneously.
Both cohorts will be enrolled simultaneously. Both cohorts have a part A (apheresis) and cohort 2 has a part B (M-CENK treatment \[one bag has a 100 mL cell suspension containing 0.25 to 0.75 x 109 cells\] and N-803 treatment). Up to 40 subjects may be enrolled in cohort 1. Subjects in cohort 1 will participate in apheresis collection of MNCs prior to receiving disease specific first-line therapy per primary oncologists' recommendations. Subjects who have completed apheresis in cohort 1 may subsequently enroll in cohort 2 part B if they have progressive disease after ≥ 2 prior therapies or if they have progressive disease within 12 months of receiving neoadjuvant or adjuvant chemotherapy. They must also meet the inclusion criteria to participate in the treatment phase (cohort 2 part B). Additionally, all subjects will be re-evaluated to confirm that they still meet the specified eligibility criteria once the M-CENK cells are manufactured and prior to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells. Up to 21 subjects may be enrolled in cohort 2 part A so that up to 11 subjects receive at least 1 dose of M-CENK. A dose is a single administration of M-CENK cells or a single administration of N-803. Subjects in cohort 2 part A will undergo an apheresis collection of MNCs prior to receiving approximately 4 weeks of disease-specific therapy per oncologists' recommendations while the M-CENK cells are being manufactured for use in the treatment phase (cohort 2 part B). Subjects will be evaluated for eligibility in inclusion/exclusion criteria prior to enrollment into part B. Additionally, all subjects will be re-evaluated to confirm that they still meet the specified eligibility criteria once the M-CENK cells are manufactured and prior to the first administration of M-CENK. The Sponsor will approve the subject's continued eligibility prior to receiving the manufactured M-CENK cells. M-CENK cells, manufactured from the autologous apheresis product, may be administered up to 10 times weekly starting on study day 1 with a minimum of 7 days between each M-CENK dose depending on the availability of cells and that there is no contra-indication to administer cells. Subjects will receive up to 5 doses of N-803 SC every 2 weeks prior to every other dose of M-CENK (ie, odd number M-CENK doses).The treatment may be administered for up to 10 doses of M-CENK, if the subject tolerates treatment, the doses of M-CENK cells are available, and the Investigator believes there may be potential benefit to the subject. Safety endpoints include assessments of TEAEs, SAEs, and clinically significant changes in safety laboratory tests, and vital signs. Toxicities will be graded using CTCAE Version 5.0, or in the case of CRS, using a specified grading system. Safety will be monitored throughout the study. The treatment of the initial 3 subjects in cohort 2 part B will be staggered with at least a 2-week interval between each subject. After the first 3 subjects in cohort 2 part B are treated, the treatment of existing subjects in cohort 2 part B will be paused after the 14-day toxicity assessment period for a safety evaluation by the Safety Review Committee (SRC). Based on the SRC safety evaluation, the treatment of the subsequent subjects can proceed if the safety evaluation from the initial 3 subjects in part B suggests that the therapy is safe. There will be another safety review after all subjects in cohort 2 have completed the 14-day toxicity assessment period.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
M-CENK will be administered up to 10 times weekly via intravenous (IV) infusion starting on study day 1 with a minimum of 7 days between each M-CENK dose. The dose of MCENK will be 0.25 - 0.75 × 10e9 cells per infusion.
N-803 15 μg/kg will be administered subcutaneously prior to every other dose of M-CENK for up to 5 doses of N-803.
Subjects in cohort 1A will participate in apheresis collection of lymphocytes (part A) and will not receive any investigational therapy in this study.
Chan Soon-Shiong Institute for Medicine
El Segundo, California, United States
Hoag Memorial Hospital Presbyterian
Newport Beach, California, United States
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by the number of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to apheresis.
\- Safety of apheresis collection as indicated by incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to apheresis, graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, or in the case of cytokine release syndrome (CRS), using the specified grading system.
Time frame: Study Day 1, assessed for up to 1 week
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by the number of participants with clinically significant laboratory tests.
\- Clinical lab tests include hematology (CBC w/ differential (5 part) including platelet count) and chemistry panel (BUN, blood urea nitrogen; CBC, complete blood count; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase) performed within 1 calendar day prior to apheresis collection. Hematology test will be performed pre- and post- apheresis collection.
Time frame: From Baseline/Screening through Study Day 1, assessed for up to 1 day
Primary Objective (cohort 1 and cohort 2, part A subjects): Determine the safety of mononuclear cell (MNC) apheresis collection by number of participants with abnormal vital signs.
\- Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation
Time frame: From Baseline/Screening through Study Day 1, assessed for up to 28 days
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of TEAEs and SAEs after the first dose of M-CENK and the first dose of N-803 (M-CENK Dose Number 1)
\- Incidence of TEAEs and SAEs, graded using the NCI CTCAE Version 5.0, or in the case of CRS using the specified grading system.
Time frame: From M-CENK Dose Number 1 up to 30 days, assessed for up to 30 days
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of participants with clinically significant laboratory tests
\- Clinical lab tests include hematology (CBC w/ differential (5 part) including platelet count) and chemistry panel (BUN, blood urea nitrogen; CBC, complete blood count; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase) performed within 1 calendar day prior to first dose.
Time frame: From M-CENK Dose Number 1, assessed for up to 1 day
Primary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of M-CENK and N-803 for SC administration by the number of participants with abnormal vital signs
\- Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation
Time frame: From M-CENK Dose Number 1, assessed for up to 1 day
Secondary Objective (cohort 1 and cohort 2, part A subjects): Evaluate the quantity and quality of the manufactured investigational cells from subjects in cohort 1 vs. cohort 2 by the number of MNCs for manufacturing M-CENK cells.
\- Number of MNCs for manufacturing M-CENK cells
Time frame: Study Day 1
Cohort 1 and cohort 2, part A subjects: Evaluate the quantity and quality of the manufactured cells from subjects in cohort 1 vs. cohort 2 by the number of MNCs collected and the % of natural killer (NK) cells.
Number of MNCs collected and the percentage of natural killer (NK) cells (CD56/CD16 positive) after a 2 blood volume apheresis collection.
Time frame: Study Day 1
Cohort 1 and cohort 2, part A subjects: Evaluate the quantity and quality of the manufactured cells from subjects in cohort 1 vs. cohort 2 by the number, phenotype (CD56/CD16 positive and CD3 positive cells), and function of M-CENK cells.
\- Number, phenotype (CD56/CD16 positive and CD3 positive cells), and function of M-CENK cells as measured by flow cytometry and interferon (IFN) γ production, and cytotoxicity following enrichment and expansion of the NK cells ex vivo.
Time frame: Study Day 1
Secondary Objective (cohort 1 and cohort 2, part A subjects): Evaluate the quantity and quality of the manufactured investigational cells from subjects in cohort 1 vs. cohort 2 by the number of cryopreserved aliquots of manufactured M-CENK cells.
\- Number of cryopreserved aliquots of manufactured M-CENK cells.
Time frame: Study Day 1
Secondary Objective (cohort 2, part B): Evaluate the overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 for SC administration in subjects with relapsed or refractory (R/R) solid tumors by the number of TEAEs and SAEs.
\- Incidence of TEAEs and SAEs, graded using the NCI CTCAE Version 5.0, or in the case of CRS using a specified grading system.
Time frame: From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months
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Cohort 2, part B subjects: Evaluate overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 in subjects with relapsed or refractory (R/R) solid tumors by the number of participants with clinically significant laboratory tests.
* Clinical lab tests include hematology (CBC w/ differential (5 part) including platelet count) and chemistry panel (BUN, blood urea nitrogen; CBC, complete blood count; RBC, red blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase) and will be performed within 1 calendar day prior to dosing. * Vital signs.
Time frame: From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months
Cohort 2, part B: Evaluate the overall safety profile of up to 10 doses of M-CENK and up to 5 doses of N-803 for SC administration in subjects with relapsed or refractory (R/R) solid tumors by the number of of participants with abnormal vital si
\- Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation
Time frame: From M-CENK Dose Number 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months
Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the objective response rate (ORR) by the percentage of subjects that achieve a confirmed complete or partial overall response
\- ORR will be measured 4 weeks after the first dose of M-CENK then every 8 weeks (± 1 week), and at EOT and EOS, in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 and modified RECIST guidelines for immunotherapy trials (iRECIST) and the percentage of subjects that achieve a confirmed complete or partial overall response will be presented. The 95% confidence interval of the response rate will be presented. Response will be assessed using both RECIST and iRECIST.
Time frame: From Baseline/Screening through End of Study (up to 12 months from first dose), measured at 4 weeks, every 8 weeks, EOT, EOS
Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the progression-free survival (PFS) by the
\- PFS will be measured 4 weeks after the first dose of M-CENK then every 8 weeks (± 1 week), and at EOT and EOS by RECIST Version 1.1 and iRECIST and will be evaluated using Kaplan-Meier methods. PFS will be defined as the time from the date of first treatment to the date of disease progression or death (any cause) whichever occurs first.
Time frame: From M-CENK Dose Number 1 to the date of disease progression or death (any cause), assessed for up to 12 months
Secondary Objective (cohort 2, part B subjects): Obtain preliminary estimates of efficacy by measuring the overall survival (OS) from the first date of treatment to the date of death.
Overall Survival will be evaluated using Kaplan-Meier methods. OS will be defined as the time from the date of first treatment to the date of death (any cause). Subjects who are alive at the end of follow-up will be censored at the last known date alive.
Time frame: From M-CENK Dose Number 1 to the date of death (any cause), assessed for up to 12 months