This study has been transitioned to CTIS with ID 2024-518627-29-00 check the CTIS register for the current data. PRIMARY OBJECTIVE• To compare the efficacy of Ampligen® versus control group / no treatment following FOLFIRINOX in subjects with…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Progression Free Survival (PFS) [Time Frame: Visit 2/ First Treatment until
disease progression, death, or end of study up to 42 months]
PFS is defined as the time, in months, from date of Visit 2/ First Treatment to
date of the first documentation of definitive disease progression as per RECIST
v1.1 (the initial progressive disease (PD)) or death due to any cause. Patients
will be classified by the investigator as having disease progression at the
time of initial imaging that meets RECIST version 1.1 criteria for disease
progression.
Secondary outcome
• Overall Survival (OS)
OS is defined as the time from date of Visit 2/ First Treatment to death due to
any cause.
• Overall Survival (OS) at 1 year
• Objective Response Rate (ORR) [Time Frame: Visit 2/ First Treatment until
disease progression per RECIST v.1.1, death, or end of study up to 42 months]
ORR is defined as the proportion of subjects who achieve a Complete Response
(CR) or Partial Response (PR) as assessed by RECIST v1.1.
• Duration of Response (DoR) [Time Frame: Visit 2/ First Treatment until
disease progression per RECIST v.1.1, death, or end of study up to 42 months]
DoR is defined as the time from the date of the first documentation of
objective tumor response (CR or PR) to the date of the first documentation of
objective tumor progression or death due to any cause, whichever occurs first.
Background summary
Pancreatic cancer is associated with an overall five-year survival of 5% and
thus contributes significantly to cancer-related mortality. A recent paper
predicted that pancreatic cancer will be the second leading cause of
cancer-related deaths before 2030 (Ansari, et. al. 2015). Currently surgery is
the only potentially curative option, but only around 15% of patients are
eligible at initial diagnosis since most pancreatic cancers are detected in an
advanced stage of the disease. Around 20% of patients are diagnosed with
locally advanced pancreatic cancer and the remaining 30-50% present with
metastatic disease (Oettle, 2014). It is clear that new treatment options are
desperately needed for this devastating malignancy.
One of these novel therapeutic options is immunotherapy which has shown to be a
promising treatment strategy. Essential in this therapeutic strategy is to
boost the patient*s immune system, by reversing the tumor-antigen specific
T-cell tolerance induced by their tumor. Toll-like receptor (TLR) agonists such
as Ampligen® (rintatolimod) are currently under investigation as adjuvants in
cancer immunotherapy clinical trials due to their ability to activate immune
cells and selectively promote inflammation. In depth analysis of the immune
parameters in patients with pancreatic cancer reveal new insights in the
interplay of these immune mechanism and survival and provide a basis/rationale
for new (immuno)therapeutic approaches and combination therapies (Vaz, et. al.
2014).
The TLR3 receptor is the primary natural danger signal for cancer and viral
infection. It is highly conserved in mammals and accordingly Ampligen® has
demonstrated its broad spectrum of both antitumor and antiviral activity across
many animal species (Strayer, et. al. 2014). The broad-spectrum anticancer
activities include complete responses in human clinical trials as a single
agent in renal cell carcinoma, melanoma, and lung cancer (NSCLC).
Study objective
This study has been transitioned to CTIS with ID 2024-518627-29-00 check the CTIS register for the current data.
PRIMARY OBJECTIVE
• To compare the efficacy of Ampligen® versus control group / no treatment
following FOLFIRINOX in subjects with Locally Advanced Pancreatic
Adenocarcinoma.
SECONDARY OBJECTIVE
• To evaluate safety and tolerability of Ampligen® following FOLFIRINOX in
subjects with Locally Advanced Pancreatic Adenocarcinoma.
EXPLORATORY OBJECTIVES
• To explore Systemic Immune-Inflammation Index (SII) as a potential biomarker
for overall survival.
• To explore associations between subject reported symptoms, functioning and
global health status/Quality of Life (QoL) using EORTC QLQ-C30 questionnaire as
well as current health status and the EQ-5D Index used in the economic
evaluation of health care using the EQ-5D-5L questionnaire.
• Evaluation of lymphocyte profile by flow cytometry in patients with
pancreatic cancer.
• To evaluate levels of tumor marker CA19-9 in patients with pancreatic cancer.
• To explore immune cell composition including B-cell and T-cell receptor
diversity, blood biomarkers including circulating tumor DNA and antibodies
against childhood immunogens, and T-cell responses to known childhood antigens
such as MMR, which may predict and/or act as pharmacodynamic indicators of
pharmacologic activity of Ampligen®.
Study design
This is a Phase 2 (proof of concept) randomized, open label, controlled,
parallel arm study to compare the safety and efficacy of Ampligen® versus
Control group / no treatment for subjects with locally advanced pancreatic
carcinoma recently completing treatment with FOLFIRINOX chemotherapy regimen*.
*Note: To be eligible for participation in this study, subjects must have
completed at least 4 months of treatment with FOLFIRINOX as part of first line
standard of care four (4) to six (6) weeks prior to screening and have not
shown evidence of disease progression per RECIST v.1.1 on CT scans, X-rays, or
MRI since last treatment.
There will be two parallel arms and approximately 90 eligible subjects will be
randomized to Ampligen® or Control/No treatment group with a 2:1 allocation.
Control Arm
The parallel control arm will be followed/no treatment until evidence of
disease progression per RECIST v.1.1. In the event of disease progression per
RECIST v.1.1, subjects in both arms can receive any standard of care treatment
option as determined by the Investigator.
The subjects will continue to be followed in this study for OS until death or
182 weeks, whichever comes first.
Subjects in both arms may continue study until they experience unacceptable
toxicity, withdraw consent, or their physician feels it is no longer in their
best interest to continue on study.
Ampligen® Arm
In this arm Ampligen® will be administered via twice weekly intravenous (IV)
infusions (e.g., Monday/Thursday or Tuesday/Friday schedule**) and subjects
will be monitored for disease progression while receiving the Ampligen®
infusions.
**Note: Schedules may be switched during a holiday/vacation week to reduce the
incidence of missed doses. The original schedule should be resumed during the
following week. At least 48 hours between doses is to be maintained. Infusions
are to be spaced with a minimum of two and a maximum of three days between
infusion days.
Subjects will continue to receive twice weekly Ampligen® treatments throughout
the duration of the study until disease progression per RECIST v.1.1 or death,
or Ampligen® is discontinued because of a safety issue or best interest of the
subject. In the event of disease progression per RECIST v.1.1, Ampligen® will
be discontinued. In the event of disease progression per RECIST v.1.1, subjects
in both arms can receive any standard of care treatment option as determined by
the Investigator.
If Ampligen® is discontinued for any reason, subjects will continue to be
followed in this study for OS until death or 182 weeks, whichever comes first.
Intervention
Please refer to study design.
Study burden and risks
RISKS / BENEFITS ASSESSMENT
Ampligen® lacks the potent toxicities seen with most chemotherapeutic cancer
drugs. In placebo-controlled Phase II/III clinical trials using the same
Ampligen® dosing schedule in patients with Chronic Fatigue Syndrome (CFS) the
incidence of Serious Adverse Events (SAEs) was the same in the placebo arm as
in the Ampligen® arm. There is no evidence of any cumulative toxicities.
This patient group has a limited life expectancy, despite the patient's burden
in the form of time investment and blood tests, we believe that finding a
possible new treatment for this patient group justifies this burden.
Furthermore, the design of the study is such that feasibility and safety are of
great importance during the implementation of the study. This reduces the
possible side effects and the safety risk to a minimum. Furthermore, the
inclusion and exclusion criteria have been designed accordingly.
Anaphylaxis/Allergic Reaction
Ampligen® is contraindicated for patients who have potentially severe allergic
reactions to any of the components of the formulation.
Administration of Ampligen® may lead to hypersensitivity reactions, including
anaphylaxis. Ampligen® contains trace quantities of protein, and although only
one possible "anaphylactic-type" reaction has been noted in over 800 patients
treated with the drug, the possibility of allergic reactions including
anaphylaxis exists. Mild rashes have been reported in several patients,
although the relationship to Ampligen® is not clear. Anaphylaxis is a serious,
acute allergic reaction requiring immediate medical attention. Thus, patients
will be closely monitored following administration and protocols will be in
place to manage should such a reaction occur.
Hepatotoxicity
A non-rintatolimod, but chemically related double-stranded RNA material, poly I
: poly C, has caused hepatotoxicity. In view of these observations, patients on
rintatolimod should be carefully observed and LFT*s will be monitored
throughout the study.
Coagulopathy
Coagulopathy, including intravascular coagulation, has been observed in a
non-rintatolimod, but chemically related double-stranded RNA material, poly I :
poly C. In view of these observations, patients on rintatolimod should be
carefully observed and Prothrombin time (PT) and activated partial
thromboplastin time (APTT) and, International Normalized Ratio (INR) will be
monitored throughout the study.
Autoimmune Disorders
Since rintatolimod is an inducer of interferons, there is the theoretical
potential that it might induce or potentiate autoimmune disease. The following
autoimmune diseases have been associated with the various interferons or poly I
: poly C, another interferon inducer of similar structure to rintatolimod:
thrombocytopenia (low platelet counts), psoriasis (skin disorder), rheumatoid
arthritis (joint disorder), hyperthyroidism (increased metabolism),
hypothyroidism (decreased metabolism), vasculitis and Raynaud*s phenomenon
(disorders of blood vessels), rhabdomyolysis and myositis (muscle disorders),
nephritis (kidney disorders), systemic lupus erythematosus and sarcoidosis
(disorders involving almost any body organ or tissue), hepatitis (liver
disorder), hemolytic anemia (red blood cell disorder), and diabetes (increased
blood sugar).
Infusion-Related Reactions
Mild and moderate reactions will be monitored more frequently and in severe and
life-threatening situations the treatment will be stopped and appropriately
treated with corticosteroids and epinephrine. Specific signs and symptoms
observed during administration will be recorded, including timing and duration.
Pregnancy/Lactation
Preliminary data suggest that rintatolimod may exert an embryotoxic effect in
rabbits and rats at doses which are below the projected therapeutic doses. In
rabbits there were dose-dependent embryotoxic effects, while in rats, the fetal
body weight was reduced. No studies have been done on the effects of
rintatolimod on pregnant or nursing women; therefore, treatment of these
individuals should not be considered. Females of childbearing potential must
have a negative pregnancy test prior to enrollment. Both male and female
patients and their partners of childbearing potential must agree to use
appropriate birth control methods throughout the study duration (excluding
women who are not of childbearing potential and men who have been sterilized).
Hormonal Replacement Therapy
One CFS patient on hormonal estradiol replacement experienced a thrombosis of
the superior vena cava (SVC) at the location of an implanted mediport catheter.
Unknown Risks
Research inherently carries the possibility of risks that are unknown or that
cannot be foreseen based on current information.
Benefits
Anticipated benefits for subjects participating in the research may include
increase in overall survival time and improvement of quality of life.
2117 SW Highway 484
Ocala 34473
US
2117 SW Highway 484
Ocala 34473
US
Listed location countries
Age
Inclusion criteria
Subjects will be eligible for enrollment in the study only if they meet ALL the
following criteria at time of Screening:
1. Histological diagnosis of pancreatic adenocarcinoma confirmed
pathologically: Unresectable pancreatic cancer; locally advanced pancreatic
cancer.
2. Measurable disease per RECIST v.1.1.
3. Completion of at least four (4) months of first line FOLFIRINOX treatment
and no disease progression per RECIST v.1.1 as confirmed by Computed Tomography
(CT) or Magnetic Resonance Imaging (MRI) scan 4 to 6 weeks after last
FOLFIRINOX treatment.
4. Male or non-pregnant, non-lactating female, >=18 years or age.
5. Negative pregnancy test for female subjects. Women of child-bearing
potential (WOCBP) and Women not of child-bearing potential are eligible to
participate. Both women of child-bearing potential and women of
non-child-bearing potential should use an approved method of birth control and
agrees to continue to use this method for the duration of the study and for 90
days after last treatment.
Acceptable methods of contraception include abstinence, female
subject/partner*s use of hormonal contraceptive (oral, implanted, or injected)
in conjunction with a barrier method (WOCBP only), female subject/partner*s use
of an intrauterine device (IUD), or if the female subject/partner is surgically
sterile or two years post-menopausal. All male subjects/partners must agree to
use a condom consistently and correctly for the duration of the study and for
90 days after last treatment. In addition, subjects may not donate sperm for
the duration of the study and for 90 days after last treatment.
Females who are less than two (2) years post-menopausal, those with tubal
ligations and those using contraception must have a negative serum pregnancy
test at baseline within the one (1) week prior to the first study medication
infusion. Every six weeks, and at study termination a pregnancy test should be
performed, either serum or urine stick test. However, if the urine result is
positive, a serum pregnancy test will be performed.
Any pregnancy that occurs while taking Ampligen® should be recorded using a
Pregnancy Report Form and reported immediately to AIM ImmunoTech, Inc.
6. Provide signed written informed consent and willingness, ability to comply
with study requirements.
7. Minimum weight of 40kg at baseline.
8. Karnofsky Performance Status of 80 or higher at baseline.
9. Subject must have a projected life expectancy of >= 3 months in the opinion
of the Investigator.
10. Subject has adequate organ function by the following laboratory assessments
at baseline (obtained <= 28 days prior to V2 / First treatment):
Hematologic
Platelets >= 100×109/L
Hemoglobin >= 9.0 g/dL
Absolute Neutrophil Count (ANC) >= 1.5×109/L
Absolute lymphocyte count >= 3 x 109/L
Hepatic
AST/ALT <= 3×ULN (if liver metastases are present, <= 5×ULN)
Alkaline phosphatase <= 2.0×ULN (if liver metastases are present, <= 5×ULN)
Total bilirubin <= 1.5×ULN
Albumin >= 3.0 g/dL
Renal
Creatinine clearance >= 60 mL/min using the Cockcroft-Gault formula. .
Coagulation
PT-INR and APTT within normal limits
Exclusion criteria
meeting ANY of the following criteria at time of Screening will be excluded
from enrollment:
1. Diagnosis of islet neoplasm acinar cell carcinoma, non-adenocarcinoma (i.e.,
lymphoma, sarcoma), adenocarcinoma originating from the biliary tree, or
cystadenocarcinoma.
2. Subjects who have surgically resectable locally advanced pancreatic
adenocarcinoma following treatment with FOLFIRINOX.
3. Subject has received prior treatment with Ampligen®.
4. Therapy with investigational drugs within 6 weeks of beginning study
medication.
5. History of prior malignancy, except for adequately treated in situ cancer,
basal cell, squamous cell skin cancer, or other cancers (e.g., breast,
prostate) for which the subject has been disease-free for at least 3 years.
Subjects with prior cancer that is adequately controlled per the judgement of
the Investigator will not be excluded from the study.
6. Any serious medical condition, laboratory abnormality, psychiatric illness,
or comorbidity that, in the judgment of the Investigator, would make the
subject inappropriate for the study.
7. Serious systemic fungal, bacterial, viral, or other infection that is not
controlled or requires intravenous (IV) treatment for infection(s).
8. Known history of positivity (regardless of immune status) for human
immunodeficiency virus (HIV).
9. Known history of, chronic active, or active viral hepatitis A, B, or C
infection
10. Clinically significant bleeding within 2 weeks prior to Randomization
(e.g., gastrointestinal [GI] bleeding, intracranial hemorrhage).
11. Pregnant or lactating women.
12. Myocardial infarction 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.
13. Subjects with abnormal electrocardiogram (ECG) at baseline QTc interval
>470 ms. Both Bazett*s and Fridericia*s corrections need to be applied; if
either is >470 ms; subject is not eligible.
14. Subjects with positive germline BRCA (gBRCA) mutations.
15. Clinically significant ascites defined as requiring >= 1 paracentesis every
2 weeks.
16. Major surgery, defined as any surgical procedure that involves general
anesthesia and a significant incision (i.e., 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.
17. Prior history of receiving immune checkpoint inhibitors (anti-CTLA4,
anti-PD1, anti-PD- L1).
18. Inability to return for scheduled treatment and assessments.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-518627-29-00 |
| EudraCT | EUCTR2022-002383-68-NL |
| ClinicalTrials.gov | NCT05494697 |
| CCMO | NL83776.078.23 |