This research study is a Phase II clinical trial study testing the safety and effectiveness
of the combination of ipilimumab, nivolumab, and radiation therapy.
The research study procedures include screening for eligibility, and study treatment
including evaluations and follow up visits.
Participants will be in this research study for as long as the study interventions are safe
and beneficial. Participants will then be followed for up to 5 years.
The names of the study interventions involved in this study are:
- Ipilimumab
- Nivolumab
- Radiation Therapy It is expected that about 30 people will take part in this research
study.
Ipilimumab and Nivolumab are both antibodies. An antibody is a protein that attaches to other
cells to fight off infection. The antibodies in ipilimumab work by not allowing cancer cell
growth. The antibodies in nivolumab work by causing programmed cell death of the cancer
cells. Radiation therapy may increase the likelihood of response to interventions like
ipilimumab and nivolumab.
The U.S. Food and Drug Administration (FDA) has not approved ipilimumab and nivolumab for
microsatellite stable pancreatic cancer. but they have been approved for other uses.
Inclusion Criteria:
- Participants must have histologically or cytologically confirmed metastatic MSS
adenocarcinoma of pancreatic origin
- Age >18 years.
- ECOG performance status <2
- Life expectancy of greater than 3 months
- Participants must have normal organ and marrow function as defined in Table 1, all
screening labs should be performed within 14 days of protocol registration.
- Hematological
- Absolute neutrophil count(ANC) ≥1000 /mcL
- White blood count (WBC) ≥2000 /mcL
- Platelets ≥75,000 / mcL
- Hemoglobin ≥7.5 g/dL
- Renal
- Serum creatinine: ≤ Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl)
OR
- Measured or calculated Creatinine clearance should be calculated per
institutional standard: ≥ 40 mL/min (if using the Cockcroft-Gault formula below):
- (GFR can also be used in place of creatinine or CrCl)
- Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum
creatinine in mg/dL
- Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum
creatinine in mg/dL
- Hepatic
- Serum total bilirubin ≤ 1.5 X ULN (subjects with Gilbert Syndrome can have a
total bilirubin <3 mg/dL
- AST (SGOT) and ALT (SGPT) ≤ 3 X ULN OR ≤ 5 X ULN for subjects with liver
metastases
- Coagulation
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT is within therapeutic
range of intended use of anticoagulants
- Activated Partial Thromboplastin Time (aPTT) ≤2.5 X ULN unless subject is
receiving anticoagulant therapy as long as PTT is within therapeutic range of
intended use of anticoagulants
- Women of childbearing potential (WOCBP) must use appropriate method(s) of
contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
days plus the time required for nivolumab to undergo five half-lives) after the last
dose of investigational drug.
- Women of childbearing potential must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG)
- Women must not be breastfeeding
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for a period of 7
months after the last dose of investigational product. Women who are not of
childbearing potential, ie, who are postmenopausal or surgically sterile as well as
azoospermic men do not require contraception
- Ability to understand and the willingness to sign a written informed consent document.
- If applicable, stable dose of dexamethasone 1.5mg or prednisone <10mg for 7 days prior
to initiation of treatment
- One previously unirradiated lesion amenable to radiotherapy 8 Gy x 3 and can meet dose
constraints, and another unirradiated measurable lesion > 1 cm in size outside the
radiation field that can be used as measurable disease. (Patients must have measurable
tumor in addition to the one being radiated.)
- Patients must have progressed on at least 1 prior line of chemotherapy. Adjuvant or
neoadjuvant therapy is permitted
Exclusion Criteria:
- Participants who have had chemotherapy, targeted small molecule therapy or study
therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤
Grade 1 or at baseline) from adverse events due to agents administered more than 2
weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion
and may qualify for the study. If subject received major surgery, they must have
recovered adequately from the toxicity and/or complications from the intervention
prior to starting therapy.
- Participants who are receiving any other investigational agents.
- Patients are excluded if they have an active, known or suspected autoimmune disease
other than those listed below. Subjects are permitted to enroll if they have vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger
- Patients are excluded if they have a condition requiring systemic treatment with
either corticosteroids (dexamethasone 1.5mg or prednisone <10mg) or other
immunosuppressive medications within 14 days of study drug administration. Inhaled or
topical steroids and adrenal replacement doses dexamethasone 1.5mg or prednisone <10mg
are permitted in the absence of active autoimmune disease. Subjects are permitted to
use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids
(with minimal systemic absorption). Physiologic replacement doses of systemic
corticosteroids are permitted, dexamethasone 1.5mg or prednisone <10mg. A brief course
of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of
non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by
contact allergen) is permitted.
- Patients are excluded if they have previously received anti-CTLA-4 therapy. Prior PD-1
or PDL1 therapy will be permitted.
- Has a known history of active TB (Bacillus Tuberculosis)
- Known HBV or HCV. (Patients are excluded if they are positive test for hepatitis B
virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody)
indicating acute or chronic infection).
- Patients are excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).These
participants are at increased risk of lethal infections when treated with marrow
suppressive therapy. Appropriate studies will be undertaken in participants receiving
combination antiretroviral therapy when indicated.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 5 months for woman and 7 months for men, after the last dose of trial
treatment.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Has received a live vaccine within 30 days of planned start of study therapy.Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- Uncontrolled brain metastases. Patients treated with radiation > 4 weeks prior with
follow up imaging showing control are eligible
