| Eligibility |
Substudy A: Inclusion Criteria:
- Patients must have histologically and/or cytologically confirmed solid tumour, that is
advanced/ metastatic/recurrent or unresectable and for which no curative therapy
exists.
- Patients must live within Canada and have received durvalumab alone, or durvalumab in
combination with tremelimumab, with or without chemotherapy/targeted therapy. Patients
who have received other anti PD-1/PD-L1 agents +/- anti CTLA agents are eligible,
providing full details of prior therapy, toxicity and management are available.
Consult with CCTG for further details.
- Patients must have previously discontinued immunotherapy due to an irAE.
- Immune-related adverse events must have resolved to = grade 1 or baseline and patient
must have completed corticosteroid therapy at least 28 days prior to registration in
this current study.
- Complete response, partial response or prolonged stable disease (SD = 8 weeks) to
initial immunotherapy. Patients that received prior adjuvant/neoadjuvant/consolidation
immunotherapy are eligible providing there has been at least a 6 month treatment free
interval prior to enrollment and patient has received at least one standard-of-care
chemotherapy regimen in the palliative setting (discuss with CCTG if chemotherapy is
not considered standard of care or not indicated or patient refused/not eligible as
such patients are eligible).
- Patients must have a life expectancy of at least 12 weeks.
- Tumour material may have already been submitted to CCTG for the initial trial. If an
additional formalin fixed paraffin embedded tissue block (from their primary or
metastatic tumour) is available from tissue collected after immunotherapy
discontinuation, patients must have provided informed consent for the release of the
block. All patients must have provided informed consent for correlative studies. If
patients from non-CCTG trials or commercial use are eventually enrolled, tumour
material is also required if available, preferably from tissue collected after
immunotherapy discontinuation.
- Presence of clinically and/or radiologically documented disease. All radiology studies
must be performed within 28 days prior to enrollment (within 35 days if negative).
Patients ideally should have measurable disease.
- ECOG performance status 0 or 1
- Previous Therapy
- Patients who received other relevant standard cancer therapies since discontinuing
immunotherapy remain eligible for inclusion as follows:
- Patients may have received prior cytotoxic chemotherapy following discontinuation
of immunotherapy for irAE.
- Patients may have received other prior therapies such as tyrosine kinase
inhibitors or other targeted agents, following discontinuation of immunotherapy
for irAE.
- Patients may not have received subsequent immune checkpoint inhibitors
(anti-PD-(L)1 and anti-CTLA-4) following discontinuation of immunotherapy for
irAE. Vaccines and oncolytic viruses are permitted.
- Patients must have recovered from all reversible toxicity related to prior
chemotherapy or systemic therapy (unless grade 1, irreversible, or considered by
investigator as not clinically significant) and have adequate washout as follows:
Longest of one of the following:
- Two weeks;
- 5 half-lives for investigational agents;
- Standard cycle length of standard therapies.
- Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks)
have elapsed between the last dose of radiation and date of enrollment. Exceptions may
be made for low-dose, non-myelosuppressive radiotherapy after consultation with CCTG.
Concurrent radiotherapy is not permitted.
- Previous surgery is permitted provided that a minimum of 28 days (4 weeks) have
elapsed between any major surgery and date of enrollment, and that wound healing has
occurred.
- Absolute neutrophils = 1.5 x 10^9/L
- Platelets = 100 x 10^9/L
- Hemoglobin = 90 g/L
- Bilirubin = 1.5 x ULN (upper limit of normal)
- AST and ALT = 2.5 x ULN - = 5.0 x ULN (if patient has liver metastases)
- Serum creatinine < 1.25 x ULN or
- Creatinine clearance = 40 mL/min
- Patient consent must be appropriately obtained in accordance with applicable local and
regulatory requirements. Each patient must sign a consent form prior to enrollment in
the trial to document their willingness to participate.
- Patients must be accessible for treatment and follow up. Patients registered on this
trial must be treated and followed at the participating centre. This implies there
must be reasonable geographical limits (for example: 1 ½ hour's driving distance)
placed on patients being considered for this trial.
- In accordance with CCTG policy, protocol treatment is to begin within 2 working days
of patient enrollment
- Women/men of childbearing potential must have agreed to use a highly effective
contraceptive method
- Subjects should not donate blood while participating in this study, or for at least 90
days following the last infusion of durvalumab
Exclusion Criteria:
- In general, patients with prior grade 4 non-hematological, non-endocrine
immune-related adverse events are not eligible.
- History of primary immunodeficiency, history of allogenic organ transplant that
requires therapeutic immunosuppression and the use of immunosuppressive agents within
28 days of enrollment.
- Live attenuated vaccination administered within 30 days prior to enrollment or within
30 days of receiving durvalumab.
- History of hypersensitivity to durvalumab or any excipient.
- Any immune-related adverse event that required biologic agents such as infliximab, or
mycophenolate motefil to manage.
- Documented progressive disease (PD) while on initial immunotherapy. Exception:
patients who had iUPD but continued on immunotherapy, and did not have documented iCPD
within 8 weeks of discontinuing immunotherapy
- 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
conduction defects). Patients with a significant cardiac history, even if controlled,
should have a LVEF = 50%.
- Concurrent treatment with other investigational drugs or anti-cancer therapy.
- 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
to:
- 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.
- Untreated symptomatic brain metastases or brain metastases in whom radiation or
surgery is indicated.
- Patients with diabetes mellitus are eligible but must be clinically stable on
therapy (if applicable) and investigator and patient should be aware of the
potential risk of immune mediated pancreatic toxicity and B cell destruction.
- Pregnant or lactating women
Substudy B: Inclusion Criteria
- Patients must be currently enrolled and receiving active treatment on a treatment arm
containing durvalumab +/- tremelimumab with or without maintenance pemetrexed with no
contraindications to continue receiving their current study regimen according to the
protocol to which the patient is currently enrolled.
- For BR.34 ONLY: patients who have disease progression (iUPD) on durvalumab may receive
one dose of tremelimumab (75 mg) along with their next durvalumab infusion as long as
all the following criteria are met:
- Patient is clinically stable
- According to the judgement of the treating physician, the patient had clinical
benefit while receiving tremelimumab in the induction phase on BR.34
- ECOG performance status of 0 or 1
- Laboratory values meet the criteria below:
Absolute neutrophils = 1.5 x 10^9/L Platelets = 100 x 10^9/L Hemoglobin = 90 g/L Bilirubin
= 1.5 x ULN (upper limit of normal)* AST and ALT = 2.5 x ULN (if liver metastases are
present, = 5.0 x ULN) Serum creatinine < 1.25 x ULN or Creatinine clearance = 45 mL/min
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