A Randomized Phase 2b/Phase 3 Study of the TGF-B2 Targeting Antisense Oligonucleotide OT-101 in Combination with FOLFIRINOX Compared with FOLFIRINOX Alone in Patients with Advanced and Unresectable or Metastatic Pancreatic Cancer

Cancer Categories

Gastrointestinal (GI)

Karmanos Trial ID

2024-003

NCT ID

NCT06079346

Age Group

Adult

Scope

National

Phase

Phase II/III

Principal Investigator

Anthony
Shields, M.D., Ph.D.
Oncology - Medical View Profile

Objective:

Part 1: Lead-in for Safety, Tolerability and PK

Primary Objective:

To determine the maximum tolerated dose (MTD) of OT-101 in patients with advanced and unresectable or metastatic pancreatic cancer when it is combined with mFOLFIRINOX.

Secondary Objective:

To characterize the PK of OT-101 when it is combined with mFOLFIRINOX in patients with advanced and unresectable or metastatic pancreatic cancer

Part 2: Randomized portion of the study

Primary Objective:

To compare the efficacy of OT-101 in combination with mFOLFIRINOX versus mFOLFIRINOX alone in patients with advanced and unresectable or metastatic pancreatic cancer as measured by overall survival (OS).

Secondary Objective:

To assess the efficacy of OT-101 in combination with mFOLFIRINOX in patients with advanced and unresectable or metastatic pancreatic cancer as measured by: · Progression-free survival (PFS) · Objective response rate (ORR), by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
To compare the safety and tolerability of OT-101 in combination with mFOLFIRINOX versus mFOLFIRINOX alone

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Eligibility

Inclusion Criteria:

A diagnosis of advanced and unresectable or metastatic pancreatic adenocarcinoma confirmed by:

Histopathology from primary tumor in pancreas, OR
Histopathology from a non-pancreatic lesion in the presence of a mass in the pancreas consistent with pancreatic adenocarcinoma or a medically documented history of pancreatic adenocarcinoma.

Measurable disease per RECIST v.1.1
Male or non-pregnant, non-lactating female, ≥18 years or age

If a female patient is of child-bearing potential, as evidenced by menstrual periods, she must have a negative serum pregnancy test (beta-human chorionic gonadotropin [β- hCG]) documented prior to the first administration of stud drugs
Female patients of childbearing age and women < 12 months since the onset of menopause must agree to use acceptable contraceptive methods for the duration of the study and 9 months following the last injection of OT-101.
Male patients must use effective contraception for a duration of 6 months after the final dose, as per the prescribing information for oxaliplatin.

Provide signed written informed consent
Eastern Cooperative Group (ECOG) Performance Status (PS) score of 0-1
Willingness and ability to comply with study requirements
Patient has adequate organ function by the following laboratory assessments at baseline(obtained ≤28 days prior to Randomization):

Hematologic

Platelets ≥100×109/L
Hemoglobin ≥9.0 g/dL
Absolute Neutrophil Count (ANC) ≥1.5×109/L
Patient has acceptable coagulation values obtained ≤28 days prior to Randomization as demonstrated by prothrombin time (PT) or international normalized ratio (INR) and partial thromboplastin time (PTT) ≤1.5× upper limit of normal (ULN) (if on Coumadin, patient must be changed to LMWH or on Factor II or Xa anticoagulant with a t½ of less than 24 hours

Hepatic

Aspartate transaminase (AST)/alanine transaminase (ALT) ≤3×ULN (if liver metastases are present, ≤5×ULN)
Alkaline phosphatase ≤2.0×ULN (if liver metastases are present, ≤5×ULN)
Total bilirubin ≤2.0×ULN (in patients with Gilbert's Syndrome total bilirubin < or = 2.5xULN)

Renal

Calculated creatinine clearance ≥50 mL/min. Actual body weight should be used for calculating creatinine clearance (e.g., using the Modification of Diet in Renal Disease [MDRD] formula. For patients with a body mass index (BMI) >30 kg/m2, lean body weight should be used instead

Patient must have a life expectancy of ≥3 months in the opinion of the Investigator

Exclusion Criteria:

Diagnosis of pancreatic islet neoplasm, acinar cell carcinoma, non-adenocarcinoma (ie,lymphoma, sarcoma), adenocarcinoma originating from the biliary tree, or cystadenocarcinoma
Patient has experienced a decrease in ECOG PS between Screening visit and within 72 hours prior to Randomization
Patient on Coumadin and not willing to change to LMWH or oral Factor II or Xa inhibitor with t½ of less than 24 hours
History of prior malignancy, except for adequately treated in situ cancer, basal cell, squamous cell skin cancer, or other cancers (eg, breast and prostate) for which the patient has been disease-free for at least 3 years. Patients with prior cancer that is adequately controlled per the judgement of the Investigator will not be excluded from the study
Any serious medical condition, laboratory abnormality, psychiatric illness, or comorbidity that, in the judgment of the Investigator, would make the patient inappropriate for the study
Patients with abnormal electrocardiogram (ECG) at baseline (QT or QTc interval >470 ms) will be excluded from this study. The eligibility of patients with ventricular pacemakers for whom the QT interval may not be accurately measurable will be determined on a case-by-case basis by the Sponsor's medical representative in consultation with the principal investigator.
Serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires intravenous antibiotics
Known history of positivity (regardless of immune status) for human immunodeficiency virus(HIV)
Known history of chronic active or active viral hepatitis A, B, or C infection
Clinically significant bleeding within 2 weeks prior to Randomization (eg, gastrointestinal[GI] bleeding or intracranial hemorrhage)
Pregnant or lactating women
Myocardial infarction, coronary bypass surgery, or arterial thromboembolic events within the last 6 months prior to Randomization, symptomatic congestive heart failure (New York Heart Association Classification >Class II, unstable angina, or unstable cardiac arrhythmia requiring medication
Clinically significant ascites defined as requiring ≥1 paracentesis every 2 weeks
Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days prior to Randomization or anticipated surgery during the study period
Prior history of receiving immune checkpoint inhibitors (anti-CTLA4, anti-PD1, anti-PD-L1)
Peripheral neuropathy (>Grade 1)
Known history of dihydropyrimidine dehydrogenase deficiency (DPD) - Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Thus, patients with a DPD deficiency are at risk of developing severe 5-FU-associated toxicity
History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner´s granulomatosis, Sjogren´s syndrome, Bell´s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, except for psoriasis not requiring systemic therapy, vitiligo or alopecia areata, or hypothyroidism
Patients receiving any of the following medications are not eligible for study:

Investigational agents other than the protocol drugs
Anti-coagulants (except for heparin to maintain the patency of central venous catheters)
Non-steroidal anti-inflammatory drugs
Clopidogrel (Plavix), dipyridamole (Persantine), or any other drug that inhibits platelet functions
Patients on greater than 2 mg dexamethasone, 10 mg Prednisone or or equivalent dose in alternate corticosteroid daily or actively undergoing corticosteroid dose escalation are NOT eligible

History of allergic reactions or known hypersensitivity to compounds of similar chemical or biologic composition to OT-101 such as anti-sense oligonucleotides or siRNA
Patients who are unable to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy. Telemedicine visits are acceptable
Not willing and able to comply with study requirements including protocol mandated procedures and visits
Other contraindications as defined in the product label of the components of the mFOLFIRINOX treatment regimen
Participation in another investigational clinical trial within 30 days of receiving the last dose of investigational study drug
Clinically significant psychiatric disorders, legal incapacity or limited legal capacity
Patients with a primary immunodeficiency

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