Determine the complete pathologic complete response (pCR) rate in patients with locally
advanced rectal adenocarcinoma.
A phase II randomized trial 3:2 with short course radiotherapy followed by mFOLFOX
chemotherapy prior to trans abdominal resection with or without an antiCD40 agonist antibody
(APX005M). There will be continuous safety assessment for at least 6 patients. Planned
accrual of 58 patients. An interim analysis after 30 patients have completed treatment and
there will be early stopping criteria for futility or efficacy. Short course radiotherapy
will consist of 5Gy x 5 to the pelvis and patients on APX005M arm will receive one infusion
during radiotherapy course, have a two week break, then start FOLFOX with APX005M in
conjunction with five out of six cycles of chemotherapy. Patients will be restaged and then
undergo definitive surgery.
1. At least 18 years of age. Both men and women and members of all races and ethnic
groups will be included.
2. Willing and able to provide written informed consent
3. Pathologic diagnosis of rectal adenocarcinoma
4. Stage III or Stage II with at least 1 of the following high-risk features:
- Distal (<1cm from anal ring)
- cT4 or within 3mm of MR fascia
- Not candidate for sphincter preservation
- Extramural venous invasion
5. No prior treatment for rectal adenocarcinoma
6. Eastern Cooperative Group (ECOG) performance status of 0-1.
7. Laboratory values supporting acceptable organ and marrow function within 21 days of
eligibility confirmation. Defined as follows:
- WBC ≥ 3,000/mL;
- ANC WBC ≥ 1,500/mL;
- PLT ≥ 100,000/mL;
- T Bili ≤ 1.5 x upper limit of normal (ULN);
- AST/ALT ≤ 2.5 x ULN;
- Creatinine not above ULN, or creatinine clearance ≥60 mL/min/1.73 m2 for
participants with creatinine levels above institutional normal.
8. Female participants of childbearing potential (FOCBP) must have a negative serum or
urine pregnancy test (per institutional standards) within 72 hours prior to the start
of study drug.
FOCBP must agree to use highly-effective method(s) of contraception (Appendix A)
during the study and for 90 days after the last dose of study drugs.
FOCBP are those who have not been surgically sterilized or have not been free from
menses for >1 year without an alternative medical cause.
9. Male participants must agree to use an adequate method of contraception (Appendix A)
starting with the first dose of study therapy through 90 days after the last dose of
1. Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any
metastatic disease by CT or PET
2. Prior RT to the pelvis.
3. Uncontrolled comorbid illness or condition including an active infection, congestive
heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would
limit compliance with the study requirements.
4. Prior treatment with any 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.
5. Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating
acute or chronic infection.
6. Any active known or suspected autoimmune disease. Participants 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 are permitted to enroll.
7. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days prior to
the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses
up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the
absence of active autoimmune disease.
8. Malignancy in the past 3 years that required active treatment except locally curable
cancers or cancers deemed by the treating physicians to not impact the subject's
9. Participants receiving any other investigational agent, standard antineoplastic
agents, or immunosuppressive agents.
10. Known history of interstitial lung disease.
11. Received live vaccine within 6 weeks prior to randomization.
12. Psychiatric illness/social situations that would limit consenting and compliance with
13. Participants who are pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
14. Patient is not a candidate for the full treatment regimen.