Phase 1 Study of Nivolumab With Ipilimumab Combined With TGFβ-15 Peptide Vaccine and Stereotactic Body Radiotherapy for Refractory Pancreatic Cancer (CheckVAC)
Phase 1 Study of Nivolumab With Ipilimumab Combined With TGFβ-15 Peptide Vaccine and Stereotactic Body Radiotherapy for Refractory Pancreatic Cancer (CheckVAC)
"Non-immunogenicity" of PC with high prevalence of immunosuppressive cells and typically a scarcity of tumor-infiltrating effector lymphocytes is considered as one of the reasons for lacking responsiveness to single-agent immunotherapies. Considering the emerging role of the tumor microenvironment, the combination of checkpoint blocking antibodies with immunomodulation of the tumor microenvironment could lead to better responses in tumor historically resistant to radiation and checkpoint blocking antibody approaches as single modalities. For example, the data from the phase 2 study CheckPAC (NCT02866383) showed durable clinical benefit in a small subgroup of patients after adding SBRT of 15 Gy to a combination of nivolumab and ipilimumab (presented at ASCO GI 2022, San Fransisco) in patients with resistant metastatic PC. Furthermore, we have found that the TGFβ-15 immune response is corelated to clinical benefit, supporting the rationale for combining of TGFβ-15 peptide vaccine with CheckPAC strategy (SBRT of 15 in combination with nivolumab and ipilimumab).
SBRT: 15 Gy x 1 on a single site of disease on day 1 cycle 1
Immunotherapy:
Nivolumab 3 mg/kg (up to 240 mg maximum) as i.v. infusion on day 1 (± 3 days) of each 14-day treatment cycle Ipilimumab 1 mg/kg as i.v. infusion on day 1 cycle 1 and subsequently every 6 weeks (± 3 days).
Vaccine (500 μl aqueous solution of 200 μg TGFβ-B-15 peptide mixed to an emulsion with 500μl Montanide ISA-51) as s.c. injection on day 1 of the first 6 cycles and subsequently every 4 weeks (± 3 days)
Inclusion Criteria:
Signed informed consent
Histological or cytological confirmation of advanced pancreatic carcinoma prior to entering this study
Prior therapy requirements:
There is no upper limit on the number of prior chemotherapy regimens received. Participants must have received and progressed during or after at least 1 line of systemic chemotherapy in the metastatic setting (gemcitabine or 5-FU based regimens).
Notes:
Age 18 years and older
ECOG Performance Status (PS) 0-1
All participants will be required to undergo mandatory pre- and on-treatment biopsies at acceptable clinical risk as judged by the investigator. An archival pre-treatment sample is not acceptable.
Participants must have normal organ and marrow function as defined below:
Women of childbearing potential (WOCBP) must use method(s) of contraception as indicated in Appendix 3. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy during the treatment and for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus thetime required for the investigational drug to undergo five half-lives. The half-life of nivolumab is up to 25 days. Men who are sexually active with WOCBP must continue contraception during the treatment and for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Women who are not of childbearing potential (i.e. who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
Subjects must have signed and dated a BIOPAC approved written informed consent form in accordance with regulatory and institutional guidelines.
Exclusion Criteria:
Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
Participants with active, known or suspected autoimmune disease. Participants are permitted to enroll with 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.
Current or prior use of immunosuppressive medication within 14 days before the first dose of nivolumab, ipilimumab and radiation in combination with TGFβ-15 peptide vaccine. The following are exceptions to this criterion:
Participants should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
Allergies and Adverse Drug Reaction
WOCBP who are pregnant or breastfeeding