Aim
The primary objective of this clinical trial is to evaluate the safety and efficacy (as measured by overall survival [OS]) of TLP0-001 in patients with pancreatic cancer refractory or intolerant to standard therapy through a comparison of the control group (placebo in combination with S-1 [tegafur/gimeracil/oteracil]) and the investigational product group (TLP0-001 in combination with S-1).
Study setting
This is an investigator-initiated, multicenter, randomized, double-blind, comparative trial. The patients are allocated to either the investigational product group or the control group in a 1:1 ratio through a central registration by dynamic allocation.
Study design
This clinical trial will be performed in accordance with the Japanese Good Clinical Practice guidelines. The schema of this trial is shown in Figure 1. Primary informed consent will be obtained from patients with advanced or recurrent pancreatic cancer who are receiving or were scheduled to receive treatment including Gemzar (Eli Lilly and Company, Indianapolis, IN) plus nab-paclitaxel and are willing to participate in this study. The patients who meet the eligibility criteria will be enrolled at primary registration. Subsequently, apheresis will be performed to collect cells for the production of the investigational product, and treatment with Gemzar plus nab-paclitaxel will be started or continued. When patients become refractory or intolerant to chemotherapy including Gemzar plus nab-paclitaxel, secondary informed consent for this study will be obtained. The patients that meet the eligibility criteria will be randomly allocated to either the investigational product group or the control group at secondary registration. Randomization will be performed using the Pocock-Simon minimization method, with allocation adjustment factors of institution and time of initial apheresis (before, during, or after primary treatment).
Investigational product
Investigational product
TLP0-001 injection: A frozen product containing 1×107 living dendritic cells per 1 mL solution, which will be thawed before use.
Control product
Placebo injection: A frozen product, which is indistinguishable from the investigational product but does not contain the active ingredient. The frozen product will be thawed before use.
Dosage and administration
The course of treatment with the investigational product in combination with S-1 will be repeated every 6 weeks as one course until the patient meets the discontinuation criteria.
For every course of treatment, S-1 will be administered for 4 weeks and then withdrawn for 2 weeks (i.e., administered every day from Day 1 to Day 28 and then withdrawn from Day 29 to Day 42). The investigational product will be administered every other week (three times, on Day 1, Day 15, and Day 29 of each course).
The investigational product will be manufactured by the organization supplying the investigational product (Tella Pharma Inc., Shinjuku, Tokyo) in accordance with Good Manufacturing Practice. The frozen investigational product will be thawed rapidly in a water-bath for approximately 70 s at 37°C at the time of administration. After the product is thawed, the contents will be directly aspirated with a syringe and administered within 1 h of thawing. The dose of the investigational product will be administered in a volume of 1000 μL. The product will be inoculated intradermally into the axilla and groin in fractional doses of 100 μL by using a syringe.
The initial dose of S-1 will be determined in accordance with the criteria presented in Table 1. S-1 will be administered in two equally divided doses (after breakfast and supper).
Treatment discontinuation criteria
The study treatment will be discontinued when a patient meets any of the following criteria during the period of administration of the investigational product:
(1) When a patient cannot start the first course of study treatment within 15 days after the secondary registration;
(2) Aggravation of the primary disease (including clinical aggravation of the primary disease without evident tumor growth by imaging studies) is observed. However, study treatment may be continued if a principal investigator judges that study treatment would be beneficial even in patients judged as progressive disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Japanese version by the Japan Clinical Oncology Group (JCOG);
(3) Diffuse alveolar damage pattern* is seen on chest imaging;
* The presence of a diffuse alveolar damage pattern is confirmed through consultation with respiratory specialists or radiologists in the hospital or specialists in the assessment of pneumonitis;
(4) When a patient with a lung lesion has pleural effusion for which a principal investigator (or co-investigator) judges as difficult to control;
(5) When an increase in pleural effusion is seen in patients with carcinomatous pleurisy;
(6) When an adverse event that requires discontinuation of the investigational product or S-1 occurs;
(1) When a patient cannot start the next course of treatment within 14 days after the scheduled date in the second course or later phases (the scheduled date is 42 days after Day 1 of the previous course. Starting the course 2 weeks after the scheduled date on the same day of the week is allowed);
(2) When an adverse event that meets the dose reduction criteria of S-1 occurs after the maximum reduction, and the attending doctor judges that discontinuation of the treatment is needed;
(3) When the attending doctor judges that discontinuation of the treatment is needed because of adverse events other than above;
(7) When administration of the investigational product is skipped twice in a row;
(8) When pregnancy is confirmed;
(9) When a patient requests to withdraw from the trial;
(10) When a patient withdraws his or her consent;
(11) When a patient has difficulty in continuing treatment because of moving, changing hospital, or is otherwise unable to attend;
(12) When a patient is found to be ineligible after registration;
Or when a principal investigator judges that discontinuation of the study treatment is needed for any other reasons.
Endpoints
[Primary endpoint]
・ OS
[Secondary endpoints]
・ Progression-free survival (PFS) according to the RECIST v1.1 Japanese version by the JCOG (judgement by an investigator, central review)
・ PFS according to the immune-related (ir) RECIST (central review)
・ Cytoreductive effect according to the RECIST v1.1 Japanese version by the JCOG (judged by an investigator, central review)
・ Cytoreductive effect according to the irRECIST (central review)
[Endpoints regarding safety]
・ Occurrence of adverse events
・ Laboratory values, vital signs, 12-lead electrocardiogram, chest computed tomography (CT) examination
[Endpoints at interim analysis]
An interim analysis for safety will be performed when six patients in the investigational product group can be included in the analysis of endpoints after the start of study treatment, and the safety for the continuation of the trial will be evaluated by the Data and Safety Monitoring Committee. The trial will be stopped if dose-limiting toxicity (DLT), for which a causal relationship with the investigational product cannot be excluded, occurs in at least three of the six patients.
Patients subjected to the analysis of primary endpoints at interim analysis will be either of the following:
(1) Patients who developed DLT, for which a causal relationship with the investigational product cannot be excluded, before the end of the first course of treatment.
(2) Patients who completed the first course of treatment with TLP0-001 in combination with S-1 without developing DLT.
[Exploratory endpoints (arbitrary tests)]
The following tests related to the exploratory endpoints are performed in specific trial sites where the tests are available. Informed consent is obtained from patients before performing any tests.
・ WT1-specific CTL (Enzyme-Linked Immuno Spot, Tetramer)
・ Intestinal flora test (fecal examination)
・ Quality of life survey (European Organization for Research and Treatment of Cancer QLQ-C30, EuroQol 5 Dimension 5 Level)
・ Investigation of tumor local environment
・ Analysis of systemic milieu in study patients
・ Analysis of the investigational product
Eligibility criteria at second registration
[Selection criteria]
(1) Having an invasive ductal pancreatic cancer (including locally advanced pancreatic cancer and recurrent pancreatic cancer) in which the diagnosis of adenocarcinoma or adenosquamous carcinoma was confirmed at the initial tissue diagnosis or cytological diagnosis, regardless of the presence or absence of measurable lesions;
(2) Patients assessed as refractory or intolerant after receiving therapy including gemcitabine plus nab-paclitaxel. Regardless of the implementation of other chemotherapy (except for fluoropyrimidine anticancer drugs) and radiation therapy;
Refractory: Aggravation of the primary disease (including clinical aggravation of the primary disease in the absence of evident tumor growth by imaging studies) is observed after receiving therapy including gemcitabine plus nab-paclitaxel (including dose reduction and cessation of treatment).
Intolerant: A condition in which a patient cannot continue the treatment, for example, owing to drug adverse reactions.
(3) Must be a minimum of 20 years of age and a maximum of 79 years of age at the time of obtaining primary informed consent;
(4) Karnofsky Performance Status score of 80 or greater;
(5) Having the following Human Leucocyte Antigen (HLA) allele types for both class I and class II:
class I: HLA-A*24:02, HLA-A*02:01, or HLA-A*02:06
class II: in HLA-DR, DRB1*04:05, DRB1*08:03, DRB1*15:01, or DRB1*15:02
in HLA-DP, DPB1*05:01 or DPB1*09:01;
(6) Life expectancy of greater than 3 months;
(7) Must meet all of the following criteria for test results during the trial preparation period, in addition, must not have received granulocyte colony-stimulating factor, erythropoietin product, blood product, or blood transfusion within 7 days before the test: (1) Leukocyte count between 3,000/mm3 and 12,000/mm3. (2) Neutrophil count of 1,500/mm3 or greater. (3) Hemoglobin level of 9.0 g/dL or greater. (4) Platelet count of 100,000/mm3 or greater. (5) Total bilirubin level of 2.0 mg/dL or lower (3.0 mg/dL or lower for patients undergoing treatment of obstructive jaundice). (6) aspartate aminotransferase level of 150 IU/L or lower (7) alanine aminotransferase level of 150 IU/L or lower. (8) Serum creatinine level of 1.2 mg/dL or lower.
(9) Creatinine clearance is 50 mL/min or greater*; * Creatinine clearance will be estimated by the Cockcroft-Gault formula, although actual measurement values will be used, if available
(8) Able to take drugs orally;
(9) Must meet the following criteria during the period from the last day of the previous treatment to the start day of the trial, where the last day of previous treatment is defined as Day 1: (1) Anticancer drug: Day 15 or later (2) Anticancer drug unapproved in Japan: Day 29 or later - In the case of antibody preparation, Day 57 or later. (3) Radiation therapy: Day 29 or later - Patients who received radiation to the administration sites (the entire axilla and groin) in this clinical trial are excluded. (4) Laparotomy: Day 15 or later (5) Systemic administration of corticosteroids: Day 15 or later;
(10) Written informed consent is obtained from the patient.
[Exclusion criteria]
(1) A history of treatment with fluoropyrimidine anticancer drugs. However, patients who underwent preoperative/postoperative adjuvant chemotherapy and have had no recurrence for at least half a year after the last day of administration of the drug can be registered;
(2) A history of receiving cancer immunotherapy including, but not limited to, activated lymphocyte therapy, dendritic cell therapy, cancer vaccine therapy, and immune checkpoint inhibitors;
(3) Having a double cancer (disease-free interval is 1 year or shorter, excluding the period of postoperative adjuvant chemotherapy). However, patients with intraepithelial cancer or intramucosal cancer lesions can be registered;
(4) A history or presence of interstitial pneumonia or pulmonary fibrosis, as confirmed by chest CT examination;
(5) A history of serious hypersensitivity to S-1 or drugs containing the ingredient;
(6) A history of hypersensitivity to OK-432, penicillin G, gentamicin, or streptomycin;
(7) A history of hypersensitivity to pig-derived ingredients or mouse-derived ingredients;
(8) A history of serious allergy including, but not limited to, severe asthma exacerbation and anaphylactic shock;
(9) Patients with watery diarrhea;
(10) Confirmed brain metastasis, or suspected from the clinical symptoms;
(11) Patients with pleural effusion, ascites, or cardiac effusion requiring puncture and drainage;
(12) Confirmed or suspected active infection;
(13) Hepatitis B Surface antigen-positive, or HBV-DNA detected by real-time Polymerase chain reaction;
(14) Positive test for Hepatitis C Virus antibody, Human T-cell Leukemia Virus Type1 antibody, Human Immunodeficiency Virus antibody, syphilis spirochete, or parvovirus (where positivity for parvovirus is determined by a DNA test);
(15) A severe mental disorder or neurological disorder;
(16) A poorly controlled* heart disease, lung disease, renal disease, or liver disease;
(17) A Common Terminology Criteria for Adverse Events Grade 4 event (including laboratory abnormalities) or other poorly controlled* comorbidities;
(18) Continuation of flucytosine, phenytoin, or warfarin potassium required;
(19) Systemic administration of the following drugs required during the period of treatment with the investigational product: (1) Corticosteroids (continuous administration) (2) Immunosuppressants, immunostimulants (3) Erythropoietin products;
(20) An autoimmune disorder requiring treatment;
(21) Investigational products (at least five doses) cannot be generated using autologous blood from apheresis performed during the period from primary registration to obtaining secondary informed consent;
(22) Participation in other clinical trials or clinical studies (except for non-interventional trials);
(23) Pregnancy or inability to discontinue breast feeding in the period starting from administration of the investigational product to 120 days after the final administration. The patient or his/her partner is unwilling to use the required methods of contraception** during the period starting from administration of the investigational product to 180 days after the final administration for men and to 120 days after the final administration for women;
(24) Others: Judged as ineligible by a principal investigator. * Common Terminology Criteria for Adverse Events Grade 3 or more as an indication **Contraception: condom, pessary, intrauterine contraceptive device, embedded contraceptive device, spermicide, vasectomy, and tubal ligation
Sample size
A clinical study by Todaka et al. showed that median survival time of patients refractory to gemcitabine receiving S-1 monotherapy was 5.8 months [19]. Based on this result, the threshold median survival time was defined as 5.8 months. In contrast, a retrospective study by the organization supplying the investigational product (Tella Pharma Inc.) showed that the median survival time of 20 patients receiving dendritic cell vaccine in combination with S-1 as secondary treatment after receiving Gemzar or Gemzar plus S-1 was 8.1 months. However, in this clinical study, the day of starting dendritic cell vaccine therapy was defined as Day 1. Given that it takes approximately 4 weeks to generate dendritic cell vaccine after the collection of cells from patients, approximately 1 month had passed from the time when the patients became refractory to Gemzar or Gemzar plus S-1 to the time of starting the vaccine therapy. In this clinical study, the dendritic cell vaccine is generated during the primary treatment, and the dendritic cell vaccine therapy in combination with S-1 is started immediately after transition to the secondary treatment (this trial). We therefore believe that it is justified to add 1 month (the period required to generate the dendritic cell vaccine) to the median OS reported by Tella Pharma Inc. Accordingly, the expected median OS is set as 9.0 months. If the median OS is 5.8 months for the control group (placebo in combination with S-1) and 9.0 months for the investigational product group (TLP0-001 in combination with S-1), the expected hazard ratio for the investigational product group relative to the control group is calculated to be 0.644. A log-rank test is used to test the null hypothesis (the hazard ratio for the investigational product group relative to the control group is 1) against the one-sided alternative hypothesis (the hazard ratio is below 1). Given the assumption of a power of 80% or higher and a two-sided significance level of 0.05, the required minimum sample size was 87 individuals per group. Accordingly, the sample size was set as 90 individuals or more per group (i.e., a total of 185 individuals) with an assumption that a few patients would become ineligible for the trial.
Observation/test/survey schedule
Tests will be performed in accordance with the following schedule. The day on which study treatment is started is defined as Day 1.
[Schedule of administration of the investigational product and combined drug/safety assessment]
Tests are performed according to the schedule of administration of the investigational product and combined drug/safety assessment (Table 2).
[Schedule of efficacy assessment/chest CT examination and exploratory assessments]
Schedule of efficacy assessment/chest CT and exploratory assessments
Tests will be performed in accordance with the schedule of efficacy assessment/chest CT examination (Table 3) and exploratory assessments (Table 4).
For these items, the day on which the first course of study treatment is started (Day 1) is used as the starting point.