QUILT-3.076: Study of Autologous M-CENK in Subjects With Locally Advanced or Metastatic Solid Tumors

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
The 2 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). A dose is a single administration of M-CENK cells or a single administration of N-803. A treatment cycle is defined as M-CENK cells that are infused on study days 1, 8, 15, and 22 in combination with subcutaneous N-803 on days 1 and 15 followed by 1 week with no treatment. In order that 10 subjects who were initially enrolled in cohort 1 and subsequently qualify for cohort 2, receive at least 1 M-CENK treatment cycle, up to 30 subjects may be enrolled in cohort 1. Subjects in cohort 1 will participate in apheresis collection of lymphocytes (part A) prior to receiving disease specific first-line therapy (if they have not received prior therapy) per primary oncologists' recommendations. Subjects in cohort 1 may subsequently enroll in cohort 2 part B while receiving standard of care (SOC) treatment. Thus, 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 (part B). In order that 10 subjects receive at least a single dose of M-CENK, up to 20 subjects may be enrolled in cohort 2. Subjects in cohort 2 will undergo an apheresis collection of lymphocytes (part A) 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 (part B). Subjects in part A will be re-evaluated for eligibility in inclusion/exclusion criteria prior to enrollment into part B. Prior to study treatment cycle 1, a washout period of 2 weeks is required to receive M-CENK cells and N-803. M-CENK cells, manufactured from the autologous apheresis product, will be infused on study days 1, 8, 15, and 22 in combination with subcutaneous N-803 on days 1 and 15, followed by one week of no treatment. Thus, assuming that sufficient doses of M-CENK are available, each cycle is a 5-week period that includes up to 4 infusions of M-CENK in combination with 2 doses of N-803 and concludes with 1 week of no treatment. In the event that fewer than 4 doses of M-CENK cells are manufactured for a subject, the subject may receive 1 to 3 doses of M-CENK cells in the first treatment cycle. In the event that more than 4 doses of M-CENK are manufactured, the subject may receive the additional cycles of M-CENK cells using the same dosing regimen. The treatment cycle may be completed up to 10 times, 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.

Official Title
-----------------
Phase 1 Open-Label Study of Autologous M-CENK in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions
-----------------
Metastatic Solid Tumor

Intervention / Treatment
-----------------
* Biological: M-CENK, Suspension for Infusion, Cryopreserved (M-CENK)
* Biological: N803
* Other: Apheresis collection of lymphocytes (part A)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years old. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. Have histologically confirmed locally advanced, unresectable, or metastatic solid tumor. For subjects with genetic mutations or alterations in solid tumors (e.g. NSCLC, pancreatic cancer, melanoma), the subjects must have received prior appropriate disease specific targeted therapy and have progressed. Have at least 1 measurable lesion and/or non-measurable disease evaluable in accordance with RECIST Version 1.1. For subjects with genetic mutations or alterations in solid tumors (eg, non-small cell lung cancer, pancreatic cancer, melanoma), the subjects must have received prior appropriate disease-specific targeted therapy and have progressed. For subjects with a history of human immunodeficiency virus (HIV) Subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/uL and without a history of AIDS defining opportunistic infections are eligible. For subjects with a history of hepatitis B virus (HBV) Subjects who are chronic carriers of HBV infection (HBsAg-positive, undetectable or low HBV DNA, and normal ALT) who are not on HBV therapy, or in individuals who have serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HBc-positive), anti-HBV prophylaxis should be assessed prior to enrollment. Subjects with chronic HBV infection with active disease who meet the criteria for anti HBV therapy should be on a suppressive antiviral therapy prior to enrollment. For subjects with a history of hepatitis C virus (HCV) Subjects with a history of HCV infection should have completed curative antiviral treatment and have a HCV viral load below the limit of quantification are eligible. Subjects who are HCV Ab positive but HCV RNA negative due to prior treatment or natural resolution are eligible. Subjects on concurrent HCV treatment and have HCV below the limit of quantification are eligible. Note: Subjects who have a history of HIV/HBV/HCV or are seropositive will require Infectious Disease Marker (IDM) testing prior to apheresis collection. Subjects who currently have non-progressive brain metastasis and were previously treated with surgical resection/debulking, radiation, and stereotactic radiosurgery. Able to undergo an Apheresis procedure: Have adequate venous access Able to sit or recline for 5-6 hours with limited movement Hemoglobin must be ≥ 9.0 g/dL Platelet count must be ≥ 100,000 cells/mm3 Vital signs must be within normal range Negative serum pregnancy test for females of childbearing potential. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Cohort 2 subjects only: Have documented progressive disease after receiving treatment with at least 2 prior lines of therapy or not be a candidate for therapy of proven efficacy for their disease. Prior immune therapy and prior treatment with a checkpoint inhibitor as per FDA indication for current standard of care therapy are allowed. Have completed a 2-week washout period following treatment with an approved chemotherapy or approved immunotherapy prior to receiving the investigational products. A repeat lab of at least 14 days after completion of the treatment to demonstrate recovery of counts to an ANC ≥ 1000, platelets ≥100,000 cells/mm3, albumin ≥ 3 g/dL, and AST/ALT within normal limits are required. The AST/ALT must be < 2.5 ULN in subjects with liver metastases. Have completed a 2-week washout period following treatment with an investigational chemotherapy or investigational immunotherapy prior to receiving the investigational products. A repeat lab of at least 30 days after completion of the treatment to demonstrate recovery of counts to an ANC ≥ 1000, platelets ≥ 100,000 cells/mm3, albumin ≥ 3 g/dL, and AST/ALT within normal limits are required. The AST/ALT must be < 2.5 ULN in subjects with liver metastases. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. Agreement to practice effective contraception for female subjects of child-bearing potential and nonsterile males. Exclusion Criteria (Cohort 1 part A): There is no exclusion criteria for Cohort 1 part A. Exclusion Criteria (Cohort 2 part B only): Serious uncontrolled concomitant disease that would contraindicate the use of the investigational drug used in this study or that would put the subject at high risk for treatment- related complications. Systemic autoimmune disease (eg, lupus erythematosus, rheumatoid arthritis, Addison's disease, autoimmune disease associated with lymphoma) requiring medical treatment Currently receiving or has received antibiotics within the last 30 days. History of organ transplant requiring immunosuppression. History of or active inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), unless the inflammation is well controlled. Inadequate organ function, evidenced by the following laboratory results: Absolute neutrophil count (ANC) < 1000 cells/mm3. Platelet count < 100,000 cells/mm3. Hemoglobin < 9 g/dL. Total bilirubin > 1.5 x the upper limit of normal (ULN; unless the subject has documented Gilbert's syndrome). AST (SGOT) or ALT (SGPT) > 2.5 × ULN (> 5 × ULN in subjects with liver metastases). Alkaline phosphatase (ALP) levels > 2.5 × ULN (> 5 × ULN in subjects with liver metastases, or >10 × ULN in subjects with bone metastases). Serum creatinine > 2.0 mg/dL or 177 μmol/L. Note: Each site should use its own institution's upper limit of normal (ULN) to determine eligibility. Subjects with ascites requiring paracentesis or pleural effusion requiring thoracentesis. Uncontrolled hypertension (systolic > 160 mm Hg and/or diastolic > 110 mm Hg) or clinically significant (ie, active) cardiovascular disease, cerebrovascular accident/stroke, or myocardial infarction within 6 months prior to first study medication; unstable angina; congestive heart failure of New York Heart Association grade 2 or higher; or serious cardiac arrhythmia requiring medication. Dyspnea at rest due to complications of advanced malignancy or other disease requiring continuous oxygen therapy. Oxygen therapy on an as needed or intermittent basis is allowed. Current chronic daily treatment (continuous for > 3 months) with systemic corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids. Short-term steroid use to prevent IV contrast allergic reaction or anaphylaxis in subjects who have known contrast allergies is allowed. Known hypersensitivity to any component of the study medication(s). Participation in an investigational drug study or history of receiving any investigational treatment or cytotoxic chemotherapy within 14 days prior to dosing for this study, except for testosterone-lowering therapy in men with prostate cancer or anti-estrogen therapy for women with breast cancer. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. Concurrent participation in any interventional clinical trial. Pregnant and nursing women. A negative serum pregnancy test during screening and a negative pregnancy test within 24 hours prior to the first dose must be documented before M-CENK is administered to a female subject of childbearing potential.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Subjects newly diagnosed no prior therapy or prior first line treatment<br>Cohort 1: Subjects with either newly diagnosed solid tumors who have not received prior therapy or subjects who have received prior first line treatment. 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 and meet the inclusion criteria for cohort 2 part B. | Other: Apheresis collection of lymphocytes (part A)<br>* Subjects in cohort 1 will participate in apheresis collection of lymphocytes (part A) and will not receive any investigational therapy in this study.<br>|
| Experimental: Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors<br>Cohort 2: Subjects with relapsed/refractory (r/r) solid tumors who have progressive disease after receiving ≥ 2 prior therapies or not a candidate for therapy of proven efficacy for their disease. | Biological: M-CENK, Suspension for Infusion, Cryopreserved (M-CENK)<br>* M-CENK will be administered 4 times via intravenous (IV) infusion on days 1, 8, 15 and 22. The dose of MCENK will be 0.25 - 0.75 × 10e9 cells per infusion.<br>Biological: N803<br>* N803 15 μg/kg will be administered subcutaneously on days 1 and 15.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 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 (treatment cycle 1, Day 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. | From Cycle 1 Day 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. | From Cycle 1 Day 1 up to 1 day, 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 | From Cycle 1 Day 1 up to 1 day, assessed for up to 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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. | 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. | Study Day 1 | 
| Secondary Objective (cohort 2, part B subjects): Evaluate the overall safety profile of up to 10 treatment cycles of M CENK and 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. | From Cycle 1 Day 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months | 
| Cohort 2, part B subjects: Evaluate overall safety profile of up to 10 treatment cycles of M-CENK and 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. | From Cycle 1 Day 1 through End of Study (up to 12 months from first dose), assessed for up to 12 months | 
| Cohort 2, part B subjects: Evaluate the overall safety profile of up to 10 treatment cycles of M CENK and N-803 for SC administration in subjects with relapsed or refractory (R/R) solid tumors by the number of of participants with abnormal vital signs. | - Vital signs to include temperature, respiratory rate, heart rate, blood pressure, and oxygen saturation | From Cycle 1 Day 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 every 8 weeks (± 1 week) 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. | From Baseline/Screening through End of Study (up to 12 months from first dose), measured every 8 weeks | 
| 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 every 8 weeks (± 1 week) 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. | From Cycle 1 Day 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. | From Cycle 1 Day 1 to the date of death (any cause), assessed for up to 12 months |