The purpose of this study is to determine the safety and effectiveness of nivolumab alone or
in combination with ipilimumab in patients with metastatic or unresectable tumors harbouring
mutations in genes, POLE and POLD1. These mutations will be determined by plasma cfDNA.
Nivolumab and ipilimumab have been given to patients across multiple types of cancer, and
safe doses and schedules have been determined.
Participants in this study have been diagnosed with metastatic or unresectable solid tumors
that have a mutation in POLE and/or POLD1. Nivolumab alone or in conjunction with ipilimumab
is predicted to be effective against tumors with POLE and/or POLD1 mutations as these genetic
changes cause increased rates of mutations in the DNA of tumor cells. These high mutation
rates have been associated with response to immunotherapy agents such as nivolumab and
- Patients must have histologically confirmed advanced (metastatic or unresectable)
- Patients must have received at least 1 standard cancer therapy for their tumor type
and progressed on their most recent regimen; patients may be treatment naïve if they
refuse standard treatment or there is no standard treatment for their cancer.
- Prior adjuvant/neoadjuvant therapy with curative intent is considered a prior therapy
if disease recurrence occurs within at least 6 months.
- Patients may not have received prior immunotherapy
- Patients must consent to blood collection for testing after registration by a central
- Patients must have clinically and/or radiologically documented disease with at least
one lesion measurable as defined by RECIST 1.1.
- Patients must be ≥ 18 years of age.
- ECOG performance status 0 or 1.
- Patients must have adequate hematology and organ function
- Patient consent for screening must be appropriately obtained in accordance with
applicable local and regulatory requirements.
- Patients must have solid tumors that demonstrate POLE or POLD1 mutations identified at
study entry via plasma cfDNA testing or tumor tissue testing for POLE and POLD1
mutations. A CLIA-certified testing of tumor tissue demonstrating POLE or POLD1
mutation can qualify for eligibility and randomization, however, plasma will be
submitted for central cfDNA testing. In the event of discordance between tissue and
central laboratory testing, the patient will continue in study but will not be
included in the primary analysis. These patients will however be included in the
- Patients must have recovered to ≤ grade 1 from all reversible toxicity related prior
systemic or radiation therapy and have a 2 weeks washout.
- Previous major surgery is permitted provided that it has been at least 28 days prior
to patient registration and that wound healing has occurred.
- White Blood Cells ≥ 2.0 x 109/L (2000/µL)
- Absolute neutrophils ≥ 1.5 x 109/L (1500/µL)
- Platelets ≥ 100 x 10^9/L (100 x103/µL)
- Hemoglobin ≥80 g/L* (8.0 g/dL)
- Bilirubin ≤ 1.5 x ULN (upper limit of normal)**
- AST and/or ALT ≤ 3 x ULN
- Serum creatinine ≤ 1.5 x ULN or: Creatinine clearance ≥40 mL/min
- Patients must be willing to consent to provision of archival tissue
- Patient consent must be appropriately obtained in accordance with applicable local and
- Patients must be willing and able to comply with scheduled visits, treatment schedule,
laboratory testing, and other requirements of the trial.
- In accordance with CCTG policy, protocol treatment is to begin within 2 working days
of patient randomization.
- Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP
must have agreed to use a highly effective contraceptive method
- Patients with a history of other untreated malignancies or malignancies, which
required therapy within the past 2 years. Patients with a prior or concurrent
malignancy whose natural history or treatment does not have the potential to interfere
with the safety or efficacy assessment of the investigational regimen may be eligible
after consultation with the CCTG.
- Patients with primary CNS tumors are not eligible.
- Patients with active brain metastases or leptomeningeal metastases are not eligible.
Patients with brain metastases are eligible if these have been treated and clinically
stable. There must also be no requirement for immunosuppressive doses of systemic
corticosteroids (> 10 mg/day prednisone equivalents). Physiologic replacement doses of
systemic corticoidsteroids are permitted, even if >10mg/day prednisone equivalents
- History of primary immunodeficiency, history of allogenic organ transplant that
requires therapeutic immunosuppression and the use of immunosuppressive agents within
14 days of study drug administration*
- Active or prior documented autoimmune or inflammatory disorders. Including,
inflammatory bowel disease (e.g. colitis or Crohn's disease), diverticulitis with the
exception of diverticulosis, celiac disease or other serious gastrointestinal chronic
conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid
arthritis, hypophysitis, uveitis, etc., within the past 3 years prior to the start of
treatment. Patients with vitiligo, type I diabetes mellitus, residual hypothyroidism
due to autoimmune condition only requiring hormone replacement, psoriasis not
requiring systemic treatment, or conditions considered to be of low risk for
recurrence are permitted to enroll.
- History of hypersensitivity to nivolumab or ipilimumab or any excipient.
- Any previous treatment with a PD-1 or anti-PD-L1, anti-PD-L2 inhibitor, including
nivolumab or an anti-CTLA4, including ipilimumab, or drug specifically targeting
T-cell stimulation or immune checkpoint pathways.
- Patients with serious illnesses or medical conditions which would not permit the
patient to be managed according to the protocol (including corticosteroid
administration), or would put the patient at risk. This includes but is not limited
- History of significant neurologic or psychiatric disorder which would impair the
ability to obtain consent or limit compliance with study requirements.
- Active infection requiring systemic therapy; (including any patient known to have
active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or
tuberculosis or any infection requiring systemic therapy).
- Active peptic ulcer disease or gastritis
- Active pneumonitis.
- Patients receiving concurrent treatment with other anti-cancer therapy or other
investigational anti-cancer agents.
- Patients who have experienced untreated and/or uncontrolled cardiovascular conditions
and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart
failure, myocardial infarction within the previous year or cardiac ventricular
arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular
- Pregnant or lactating women.
- Men who are sexually active with women of childbearing potential and women of
childbearing potential must agree to use adequate contraception.