None listed
Conditions
Brief summary
Ovarian cancer is the second most common gynaecological malignancy and the most common cause of gynaecological cancer death in Australia. The majority of women are diagnosed with advanced disease, where standard treatment includes surgery followed by six cycles of adjuvant platinum-based chemotherapy. The purpose of this research project is to test how safe and effective the combination treatment of durvalumab and tremelimumab in combination with standard chemotherapy is as a treatment for patients with ovarian, fallopian tube or peritoneal cancers. Who is it for? You may be eligible to join this study if you are a female aged 18 years or older with a confirmed diagnosis of stage III or IV high grade serous ovarian, fallopian tube, or peritoneal carcinoma, and a life expectancy of at least 12 weeks. Study details Participants in this study will be randomly allocated (by chance) to one of two groups. Participants in one group will receive [18 weeks/6 cycles] of treatment with Carboplatin, paclitaxel combined with durvalumab and tremelimumab (Du-T-NACT) administered intravenously (i.e. directly into the vein). This will then be followed by maintenance therapy with Durvalumab (every 4 weeks) and Tremelimumab (every 12 weeks) for 36 weeks or until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Durvalumab and tremelimumab are new drugs which are designed to increase the body’s immune response. Participants in the other group will receive [18 weeks/6 cycles] of chemotherapy with Carboplatin and paclitaxel only, followed by an observation period, which involves 4 weekly CA-125 assessments. Participants in both groups may also undergo interval debulking surgery after 3 cycles of treatment, if suitable. All participants will be monitored regularly for up to 12 months post treatment in order to assess clinical response and treatment safety. It is hoped that that durvalumab and tremelimumab will stimulate the immune cells to be able to prevent or slow down cancer growth. The study aims to recruit 75 patients (50 patients to receive adjuvant treatment and 25 to receive neoadjuvant treatment at a 2:1 ratio), across 10 Australian sites over a 2 year recruitment period.
Interventions
Participants will be randomised in the ratio of 2:1 between the Arms:
Arm 1: Carboplatin, paclitaxel combined with durvalumab and tremelimumab (Du-T-NACT), followed by maintenance durvalumab and tremelimumab
a) Carboplatin: AUC 5 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks
b) Paclitaxel: 175 mg/m2 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks
c) Durvalumab: 1500mg via intravenous infusion on Day 1 of each 21 day cycle, for
Participants will be randomised in the ratio of 2:1 between the Arms: Arm 1: Carboplatin, paclitaxel combined with durvalumab and tremelimumab (Du-T-NACT), followed by maintenance durvalumab and tremelimumab a) Carboplatin: AUC 5 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks b) Paclitaxel: 175 mg/m2 via intravenous infusion on Day 1 of each 21 day cycle, for a total of 18 weeks c) Durvalumab: 1500mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks d) Tremelimumab: 75mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks Following completion of 3 cycles of neoadjuvant treatment, patients in both arms who are suitable for interval debulking surgery (IDS) should undergo debulking surgery with the goal of optimal cytoreduction by a certified gynaecological oncologist. Surgery should be performed at least 21 days after cycle 3 day 1 (C3D22) but before day 36 (C3D36) provided adequate haematological and clinical recovery. Patients in Arm 1 who continue to respond will receive maintenance therapy with durvalumab and tremelimumab. Maintenance treatment should commence 4 weeks ± 3 days following the last dose of adjuvant treatment in cycle 6 and continue for 36 weeks or until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Maintenance immunotherapy will consist of: a) Durvalumab: 1500mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks b) Tremelimumab: 75mg via intravenous infusion on Day 1 of each 21 day cycle, for a total of 36 weeks
Sponsors
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed, written informed consent obtained from the patient prior to performing any protocol-related procedures, including screening evaluations 2. Age greater than or equal to 18 years at the time of screening 3. Has a life expectancy of at least 12 weeks 4. Histologically or cytologically confirmed high grade serous ovarian carcinoma 5. FIGO stage IIIC or IV disease: - A diagnosis of stage IIIC requires evidence of macroscopic, extra-pelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen. based on either laparoscopic or radiological assessment - Stage IV disease is defined as either IVA: pleural effusion with positive cytology, or IVB: hepatic and/or splenic parenchymal metastasis, metastasis to extraabdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity) 6. Agree to undergo a pre-treatment biopsy either radiologically (core-needle) or via laparoscopy. Fine needle aspirate (FNA) alone is not acceptable. 7. Measurable disease according to RECIST 1.1 criteria 8. Considered to be both medically fit to receive NACT, and a suitable surgical candidate for interval debulking surgery by both the study investigator and the treating gynaecologic oncologist 9. ECOG performance status 0-1 10. Adequate normal organ and marrow function as defined below: - Haemoglobin greater than or equal to 90g/L - Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L - Platelet count greater than or equal to 100 x 109/L - Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilberts syndrome (persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology, who will be allowed only in consultation with the CPI - AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x ULN unless liver metastases are present, in which case it must be less than or equal to 5 x ULN - Measured creatinine clearance (CL) >40mL/min or Calculated creatinine clearance >40mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance - Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. 11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing biopsies, treatment, and scheduled visits and examination including follow up 12. Body weight >30 kg
Exclusion criteria
1. Previous chemotherapy, radiotherapy or surgery for ovarian cancer 2. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti PD 1, anti-PD-L1, or anti-PD-L2 antibodies, including therapeutic anticancer vaccines. 3. Prior omentectomy 4. Patients with disease that is considered inoperable and in the opinion of the treating gynaecological oncologist is unlikely to become operable post NACT 5. Participation in another clinical study with an investigational product during the last 6 months 6. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study 7. Any unresolved toxicity NCI CTCAE Grade greater than or equal to 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria - Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the CPI 8. Any other concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non–cancer-related conditions (e.g., hormone replacement therapy) is acceptable 9. Major surgical procedure within 28 days prior to randomisation. A diagnostic laparoscopy or laparotomy is acceptable provided a debulking has not been performed. 10. History of allogenic organ transplantation 11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., ulcerative colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: - Patients with vitiligo or alopecia - Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement - Any chronic skin condition that does not require systemic therapy - Patients without active disease in the last 5 years may be included but only after consultation with the CPI - Patients with coeliac disease controlled by diet alone 12. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent 13. History of another primary malignancy except for - Malignancy treated with curative intent and with no known active disease greater than or equal to 5 years before the randomisation and of low potential risk for recurrence - Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease - Adequately treated carcinoma in situ without evidence of disease 14. History of leptomeningeal carcinomatosis 15. Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to randomisation 16. History of active primary immunodeficiency 17. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative) 18. Current or prior use of immunosuppressive medication within 14 days before randomisation. The following are exceptions to this criterion: - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent - Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) 19. Receipt of live attenuated vaccine, inactive vaccines including annual influenza vaccine within 30 days prior to randomisation. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study drugs and up to 30 days after the last dose of study drugs 20. Patients who are pregnant or breastfeeding or of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab and tremelimumab combination therapy 21. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients 22. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment Arm assignment..
Outcome results
None listed