Open-Label, Phase 1 Clinical Trial of Neoadjuvant Nogapendekin Alfa Inbakicept, Sotevtamab, and Zabadinostat in Combination With Gemcitabine and Nab-Paclitaxel for Participants With Borderline Resectable or Locally Advanced Pancreatic Cancer

Phase 1Not Yet RecruitingNCT07488884

ImmunityBio, Inc.30 enrolled

Overview

This is an open-label, phase 1 clinical trial to evaluate the safety and preliminary efficacy of neoadjuvant chemoimmunotherapy (NAI, sotevtamab, and zabadinostat in combination with gemcitabine and nab-paclitaxel) followed by resection and adjuvant immunotherapy for participants with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC). Eligible participants will undergo endoscopic ultrasound (EUS)-guided biopsies of the primary pancreatic tumor within 7 days of enrollment and prior to study day 1. EUS-guided biopsies will be used for histopathological examination to give clinical diagnostic information (as SoC) and will be stored in an ethically approved tissue bank.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pancreatic Cancer Resectable Pancreatic Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 18 years old. 2. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. 3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 4. Histologically or cytologically confirmed PDAC that is confined to the pancreas. 5. Borderline resectable (surgical resection possible but challenging) or locally advanced (surgical resection not possible) PDAC, as determined by the local investigator based onlocal institutional guidelines. 6. Measurable tumor lesions according to RECIST v1.1. (within 90 days prior to first dose of study treatment). 7. Have not received prior anticancer therapy for pancreatic cancer. 8. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 9. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Female participants of child-bearing potential must agree to use effective contraception for up to 7 months after completion of therapy, and nonsterile male participants must agree to use a condom for up to 7 months after treatment. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables, 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy. Exclusion Criteria: 1. Resectable PDAC, meeting the following criteria upon CT/MRI: (a)No superior mesenteric vein (SMV) or portal vein (PV) distortion; (b) Clear fat planes around superior mesenteric artery (SMA), celiac artery (CA), and common hepatic artery (CHA). 2. Participants for whom an operation is not considered in the participant's best interest (eg, due to comorbidity). 3. Histologically or cytologically confirmed pancreatic tumor that is not adenocarcinoma. 4. CA19-9 \> 1,000 U/mL. 5. QTc interval using Fridericia's formula (QTcF) \> 470 ms. 6. If participants have had major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. 7. Have received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed. 8. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 9. Inadequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to baseline: (a) Absolute neutrophil count (ANC) \< 1,500 cells/μL without granulocyte colonystimulating factor support, (b) Lymphocyte count \< 500/μL, (c) platelet count \< 100,000/μL without transfusion (d) Hemoglobin \< 8.0 g/dL Note: Participants may be transfused to meet this criterion, (e) International Normalized Ratio (INR) or aPTT activated partial thromboplastin time (aPTT) \< 1.5 × upper limit of normal (ULN) Note: This applies only to participants who are not receiving therapeutic anticoagulation; participants receiving therapeutic anticoagulation should be on a stable dose. (f) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase \> 2.5 × ULN, with the following exception: Participants with documented liver metastases: AST and/or ALT \> 5 × ULN. (g) Serum bilirubin ≤ 3 × ULN (h) Creatinine clearance ≤ 60 mL/min (calculated using the Cockcroft-Gault formula), (i) Serum albumin ≤ 3.0 g/dL. (j) Urine dipstick for proteinuria \> 2+ (within 7 days prior to initiation of study treatment). Participants with ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \< 1 g of protein in 24 hours. 10. Significant cardiovascular disease (such as New York Heart Association cardiac disease class II or greater), myocardial infarction within 3 months prior to baseline, unstable arrhythmias, or unstable angina. 11. Severe infections at the time of enrollment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. 12. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 13. Prior allogeneic bone marrow transplantation or solid organ transplant. 14. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications. 15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. 16. Treatment with systemic immunosuppressive medications (including, but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to initiation of study treatment, or anticipation of the need for systemic immunosuppressive medication during study treatment, with the following exceptions: (a) A. Participants who have received acute, low-dose, systemic immunosuppressant medications (eg, a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Medical Monitor, (b)B. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (eg, fludrocortisone) for participants with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. 17. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to the start of treatment on this study. 18. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. 19. Pregnant and nursing women.

Outcomes

Primary Outcomes

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Number of participants experiencing ≥1 treatment-emergent adverse event (TEAE) and ≥1 serious adverse event (SAE), graded per NCI CTCAE v5.0. Adverse events will be coded using MedDRA. Analyses will be performed in the safety population (all participants receiving ≥1 dose of study treatment).

Time frame: From first dose through 30 days after last dose (SAEs and immune-related AEs followed for 90 days after last dose); survival/safety follow-up through 104 weeks (2 years) post last dose.

Clinically important changes in laboratory tests and vital signs

Number and percent of participants with protocol-defined clinically important laboratory abnormalities (hematology, chemistry including liver/renal, coagulation) or vital-sign changes that meet action criteria or result in dose modification, treatment interruption, or discontinuation; summarized by grade and action taken.

Time frame: Baseline (pre-dose) through 30 days after last dose (clinically important labs/vitals and related actions); SAE/irAE follow-up 90 days; long-term follow-up through 104 weeks (2 years) post last dose.

Secondary Outcomes

RFS, defined as time from surgical resection to disease recurrence or death from any cause, whichever occurs first, by RECIST v1.1.

Recurrence-free survival (RFS) measured by RECIST v1.1: time (days) from surgical resection to first documented disease recurrence (radiographic per RECIST v1.1, confirmed per protocol) or death from any cause. Tumor assessments per protocol imaging schedule (every 8 weeks ±1 week) and iRECIST guidance for immune-related events; participants initiating new anticancer therapy or completing follow-up without recurrence are censored at last documented recurrence-free date. Report Kaplan-Meier curve, median RFS and 95% CI, and number (%) of events and censored observations.

Time frame: From date of surgical resection until documented disease recurrence or death from any cause, whichever occurs first; participants censored at last disease assessment or at 104 weeks (2 years) post last dose.

R0 resection rate, defined as the percentage of cases having a pathologically complete resection with a negative resection margin.

Percentage of participants with a pathologically confirmed R0 resection (complete resection with negative margins). Report n and %, and exact 95% Clopper-Pearson CI.

Time frame: At time of surgical resection (performed within 8 months of first study dose).

ORR by RECIST v1.1

Objective response rate (confirmed CR or PR per RECIST v1.1, confirmation ≥4 weeks after initial response). Report n and %, 2-sided exact 95% CI, and best overall response distribution.

Time frame: From first study treatment until documented objective response or censoring; tumor assessments every 8 weeks (±1 week) through last treatment dose and per follow-up schedule through 104 weeks.

DOR by RECIST v1.1.

Duration of response for participants with confirmed CR/PR by RECIST v1.1. Analyze by Kaplan-Meier; present median DOR and 95% CI, KM curve, and numbers at risk.

Time frame: For responders, from date of first documented CR/PR to date of documented progression or death (any cause); follow until event or censoring through 104 weeks.

Immune Recurrence-Free Survival (iRFS) by iRECIST

Immune recurrence-free survival (iRFS), defined as time from surgical resection to immune-confirmed recurrence (iCPD per iRECIST) or death from any cause, whichever occurs first. iRFS will be analyzed using Kaplan-Meier methods, with median iRFS and two-sided 95% confidence intervals summarized.

Time frame: From date of surgical resection until immune-confirmed progression (iCPD), death, or censoring, with imaging every 8 weeks (±1 week) through 104 weeks after last dose.

Immune Objective Response Rate (iORR) by iRECIST

Immune objective response rate (iORR), defined as the proportion of participants with a confirmed immune complete response (iCR) or immune partial response (iPR) per iRECIST. Best overall immune response will be determined, and iORR with two-sided 95% confidence intervals will be summarized.

Time frame: From first dose until immune-confirmed progression (iCPD), death, or censoring, with imaging every 8 weeks (±1 week) through 104 weeks after last dose.

Immune Duration of Response (iDOR) by iRECIST

Immune duration of response (iDOR), defined for participants with a confirmed iCR or iPR per iRECIST as the time from the first documented iCR/iPR to immune-confirmed progression (iCPD) or death from any cause, whichever occurs first. iDOR will be analyzed using Kaplan-Meier methods, with median iDOR and two-sided 95% confidence intervals summarized. Time Frame:

Time frame: From first confirmed iCR or iPR until immune-confirmed progression (iCPD), death, or censoring, with imaging every 8 weeks (±1 week) through 104 weeks after last dose.

OS, defined as time from start of study treatment to death resulting from any cause.

Overall survival assessed by Kaplan-Meier. Present OS curve, median OS with 95% CI, number (%) of deaths, and survival rates at prespecified timepoints.

Time frame: From date of first study treatment to death from any cause; participants censored at last known alive date; follow through 104 weeks (2 years) post last dose (or longer if protocol specifies).

Major pathologic response, defined as CAP TRG of 0 or 1 at the time of surgical resection.

Proportion of resected participants with major pathologic response defined as CAP Tumor Regression Grade 0 or 1 on surgical specimen. Report n and %, and exact 95% CI; provide distribution of CAP TRG scores.

Time frame: At time of surgical resection (tissue collected at resection).

Biochemical response, defined as > 50% decrease in CA 19-9 from baseline

Proportion of participants achieving a biochemical response, defined as \>50% decrease in CA 19-9 from baseline. Report n and %, 95% CI, timing to response, and summary statistics (median percent change, time to nadir).

Time frame: From baseline (pre-treatment) through the earliest of disease recurrence/progression, start of new anti-cancer therapy, or 104 weeks after last dose; CA 19-9 measured at baseline and on Day 1 of each 28-day treatment cycle.

Whole Slide Image Availability for Exploratory Image-Outcome Analyses

Number of participants with evaluable high-resolution whole slide images (H\&E-stained tumor tissue, digital or scanned slides) collected for exploratory analyses. Slides may undergo quantitative histomorphometry, immune/tumor microenvironment characterization, and AI/algorithmic feature extraction. Image-derived features will be analyzed in relation to clinical and pathologic outcomes (e.g., RFS, iRFS, ORR/iORR, DOR/iDOR, OS, CAP TRG) and biomarker data (ctDNA, CA 19-9) using prespecified statistical methods (e.g., multivariable models, supervised/unsupervised learning with adjustment for key covariates). For this Outcome Measure, the primary metric is the number of participants with at least one evaluable whole slide image available for such analyses.

Time frame: From baseline diagnostic biopsy (screening) and/or surgical resection up to End-of-Treatment (EOT), assessed up to 104 weeks after first dose.

Blood for ctDNA analysis.

Number of participants with evaluable plasma specimens for circulating tumor DNA (ctDNA) analysis. Blood will be collected for tumor-informed and/or tumor-agnostic ctDNA assays to profile somatic alterations and quantify ctDNA levels. For this Outcome Measure, the primary metric is the number of participants with at least one evaluable ctDNA sample at any protocol-specified collection time point.

Time frame: From baseline and Day 1 of neoadjuvant Cycles 3 and 5 (each cycle is 28 days), Day 1 of adjuvant Cycle 1 (28-day cycle), and Day 1 of every third adjuvant cycle thereafter, through End-of-Treatment (EOT), assessed up to 104 weeks after last dose.