Gemcitabine and Nab-Paclitaxel vs Gemcitabine, Nab-Paclitaxel, Durvalumab and Tremelimumab as 1st Line Therapy in Metastatic Pancreatic Adenocarcinoma
Condition: Pancreatic Adenocarcinoma
MeSH terms: Adenocarcinoma
Intervention: Gemcitabine; Nab-paclitaxel; Durvalumab; Tremelimumab
Intervention MeSH terms: Paclitaxel; Gemcitabine; Durvalumab; Tremelimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 180.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The standard or usual treatment for this disease consists of two chemotherapy drugs
      gemcitabine and nab-paclitaxel given together.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed pancreatic ductal
             adenocarcinoma which is metastatic.

          -  Must have presence of measurable or evaluable disease as defined by Response
             Evaluation Criteria in Solid Tumours (RECIST 1.1).

          -  Patients must be considered suitable candidates for, and able to receive, first line
             chemotherapy for metastatic disease with gemcitabine and nab-paclitaxel.

          -  Patient must consent to provision of, and investigator(s) must confirm access to and
             agree to submit within 4 weeks of randomization to the CCTG Central Tumour Bank, a
             representative formalin fixed paraffin block of tumour tissue of adequate amount and
             quality in order that the specific correlative marker assays proscribed in the
             protocol may be conducted.

          -  Patient must consent to provision of samples of blood, serum and plasma in order that
             the specific correlative marker assays proscribed may be conducted.

          -  Patients must be ≥ 18 years of age.

          -  Patients must have an ECOG performance status of 0 or 1 with a life expectancy of at
             least 12 weeks.

          -  No prior treatment for metastatic disease is permitted. Patients may have received
             prior adjuvant chemotherapy if the last dose was given more than 6 months prior to
             recurrence. Patients may not have received chemoradiotherapy or adjuvant radiation
             therapy. Patient may not have received nab-paclitaxel as adjuvant therapy. Prior
             systemic treatment for borderline resectable or locally advanced disease is not
             permitted. Patients receiving a single dose of radiation (up to 8Gy/800RAD) with
             palliative intent for pain control are eligible provided a minimum of 14 days have
             elapsed between the radiation and the date of randomization.

          -  Adequate normal organ and marrow function as defined below (must be done within 14
             days prior to registration).

        Absolute neutrophils ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Hemoglobin ≥90 g/L Bilirubin ≤
        1.5 x upper normal limit AST and ALT ≤ 2.5 x upper normal limit Serum creatinine <1.25 UNL
        or Creatinine clearance ≥40mL/min

          -  Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as
             necessary to document all sites of disease done within 28 days prior to randomization.

          -  Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life
             questionnaires in either English or French.

          -  Patient consent must be appropriately obtained in accordance with applicable local and
             regulatory requirements.

          -  Patients must be accessible for treatment and follow-up. Patients registered on this
             trial must be treated and followed at the participating centre. Patients must agree to
             return to the participating centre for management of any adverse events which may
             occur through the course of the trial. This implies there must be reasonable
             geographical limits placed on patients being considered for this trial. Sites are
             encouraged to contact CCTG (or their respective Cooperative Group for sites outside
             Canada) for any questions regarding the interpretation of this criterion.
             Investigators must assure themselves the patients randomized on this trial will be
             available for complete documentation of the treatment, adverse events, and follow-up.

          -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
             of patient randomization.

          -  Women/men of childbearing potential must have agreed to use a highly effective
             contraceptive method

        Exclusion Criteria:

          -  Patients with a history of other malignancies, except: adequately treated non-melanoma
             skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours
             curatively treated with no evidence of disease for ≥ 5 years. Patients with a history
             of other malignancies detected at an early stage and whom the investigator believes
             have been curatively treated and are at a low risk of recurrence MAY be eligible.
             Contact CCTG to discuss eligibility prior to enrolling.

          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
             anti-CTLA4, including tremelimumab.

          -  History of primary immunodeficiency, history of organ transplant that requires
             therapeutic immunosuppression or prior history of severe (grade 3 or 4)
             immune-mediated toxicity from other immune therapy.

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             planned dose of study therapy, with the exceptions of intranasal and inhaled
             corticosteroids or systemic corticosteroids at physiological doses, which are not to
             exceed 10 mg/day of prednisone, or an equivalent corticosteroid.

          -  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 polyangitis), rheumatoid arthritis,
             hypophysitis, uveitis, etc. within the past 3 years prior to the start of treatment.
             The following are exceptions to this criterion:

               -  Patients with alopecia

               -  Patients with Grave's disease, vitiligo or psoriasis not requiring systemic
                  treatment (within the last 2 years).

               -  Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
                  hormone replacement.

        NOTE: Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic
        treatment (within the past 2 years) are not excluded.

          -  Patients with active or uncontrolled intercurrent illness including, but not limited
             to:

               -  cardiac dysfunction (symptomatic congestive heart failure, uncontrolled
                  hypertension, unstable angina pectoris, cardiac arrhythmia);

               -  active peptic ulcer disease or gastritis;

               -  active bleeding diatheses;

               -  psychiatric illness/social situations that would limit compliance with study
                  requirements or compromise the ability of the subject to give written informed
                  consent;

               -  known history of previous clinical diagnosis of tuberculosis;

               -  known human immunodeficiency virus infection (positive HIV 1/2 antibodies);

               -  known active hepatitis B infection (positive HBV surface antigen (HBsAg)).
                  Patients with a past or resolved HBV infection (defined as presence of hepatitis
                  B core antibody (anti-HBc) and absence of HBsAg) are eligible;

               -  known active hepatitis C infection. Patients positive for hepatitis C (HCV)
                  antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

          -  History of leptomeningeal carcinomatosis.

          -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
             of but not limited to surgery, radiation and/or corticosteroids.

          -  Receipt of live attenuated vaccination (examples include, but are not limited to,
             vaccines for measles, mumps, and rubella, live attenuated influenza vaccine (nasal),
             chicken pox vaccine, oral polio vaccine, rotavirus vaccine, yellow fever vaccine, BCG
             vaccine, typhoid vaccine and typhus vaccine) within 30 days prior to randomization.

          -  Pregnant or lactating women.

          -  Any active disease condition which would render the protocol treatment dangerous or
             impair the ability of the patient to receive protocol therapy.

          -  Any condition (e.g. psychological, geographical, etc.) that does not permit compliance
             with the protocol.

          -  History of hypersensitivity to gemcitabine, nab-paclitaxel, durvalumab or tremelimumab
             or any excipient.