Clinical trial NCT02879318: Gemcitabine and Nab-Paclitaxel vs Gemcitabine, Nab-Paclitaxel, Durvalumab and Tremelimumab as 1st Line Therapy in Metastatic Pancreatic Adenocarcinoma
Official title: A Randomized Phase II Trial of Gemcitabine and Nab-Paclitaxel vs Gemcitabine, Nab-Paclitaxel, Durvalumab and Tremelimumab as 1st Line Therapy in Metastatic Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pancreatic Adenocarcinoma
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: AstraZeneca
First posted: 2016-08-25
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: Durvalumab is a new type of drug for many types of cancer. Laboratory tests show that it works by allowing the immune system to detect cancer and reactivate the immune response. This may halp to slow down the growth of cancer or may cause cancer cells to die. Durvalumab has been shown to shrink tumours in animals and has been studied in a few people and seems promising but it is not clear if it can offer better results than standard treatments alone.

Tremelimumab is a new type of drug for various types of cancers. It works in a similar way to durvalumab and may improve the effect of durvalumab. This may also help slow the growth of the cancer cells or may cause cancer cells to die. Tremelimumab has been shown to shrink tumours in animals and has been studied in a few people and seems promising but it is not clear if it can offer better results than standard treatment alone when used with durvalumab.

Combination of durvalumab and tremelimumab have also been studied and when combined have been shown to increase tumour shrinkage in animals compared to either drug alone and while the combination has been studied in a few people, it is not clear if it can offer better results than standard treatment.

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.

Primary outcomes:
measure: Overall Survival
timeFrame: 35 months
Secondary outcomes:
measure: Progression Free Survival
timeFrame: 35 months
measure: Objective Response Rate
timeFrame: 35 months
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Moncton
country: Canada
facility: The Vitalite Health Network - Dr. Leon Richard
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Regional Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Laval
country: Canada
facility: Hopital de la Cite-de-la-Sante
state: Quebec
city: Levis
country: Canada
facility: L'Hotel-Dieu de Levis
state: Quebec
city: Montreal
country: Canada
facility: CHUM-Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: The Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: The Research Institute of the McGill University
state: Quebec
city: Montreal
country: Canada
facility: Centre Integre Universitaire De Sante Et De Services
state: Quebec
city: Quebec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
Study officials:
affiliation: Ottawa Hospital Research Institute, ON Canada
name: Derek Jonker
role: STUDY_CHAIR
References:
citation: Renouf DJ, Loree JM, Knox JJ, Topham JT, Kavan P, Jonker D, Welch S, Couture F, Lemay F, Tehfe M, Harb M, Aucoin N, Ko YJ, Tang PA, Ramjeesingh R, Meyers BM, Kim CA, Du P, Jia S, Schaeffer DF, Gill S, Tu D, O'Callaghan CJ. The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma. Nat Commun. 2022 Aug 26;13(1):5020. doi: 10.1038/s41467-022-32591-8.