None listed
Conditions
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of durvalumab plus chemotherapy in patients with with extra-pulmonary small cell carcinoma. Who is it for? You may be eligible to join the study if you are aged 18 years and older and have recently been diagnosed with extra-pulmonary small cell carcinoma. Study details Participants will receive durvalumab and chemotherapy. Durvalumab is given by infusion every three weeks, and chemotherapy will be given by infusion every three weeks for the first 4 doses. After the combination completes, you will receive durvalumab every 4 weeks, for as long as you are tolerating the treatment well and the cancer is under control. Participants will undergo clinical assessments at 3-4 weekly intervals from first treatment until end of treatment. Safety and tolerability of treatment will be assessed at 3-4 weekly intervals. Health related quality of life during treatment will be assessed at 3-4 weekly intervals while on treatment and then every 8 weeks after end of treatment until progression. We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that durvalumab and chemotherapy will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Interventions
The intervention has two phases:
1. Induction treatment: During induction, participants will receive four cycles of chemotherapy plus durvalumab every 3 weeks.
a. Chemotherapy: either cisplatin 75mg/m2 OR carboplatin AUC 5 via intravenous infusion on day 1 of each cycle AND etoposide 100mg/m2 via intravenous infusion OR etoposide 200mg/m2 oral capsule OR Etopophos 113.6mg/m2 intravenous infusion on days 1-3 of each cycle.
b. Durvalumab: 1500mg via intravenous infusion on day 1 of each cycle.
T
The intervention has two phases: 1. Induction treatment: During induction, participants will receive four cycles of chemotherapy plus durvalumab every 3 weeks. a. Chemotherapy: either cisplatin 75mg/m2 OR carboplatin AUC 5 via intravenous infusion on day 1 of each cycle AND etoposide 100mg/m2 via intravenous infusion OR etoposide 200mg/m2 oral capsule OR Etopophos 113.6mg/m2 intravenous infusion on days 1-3 of each cycle. b. Durvalumab: 1500mg via intravenous infusion on day 1 of each cycle. The four cycles of chemotherapy are inclusive of the one cycle permitted within 3 weeks of enrolment. 2. Maintenance treatment: During the maintenance phase, participants receive durvalumab 1500mg via intravenous infusion every 4 weeks until disease progression, toxicities, or at Investigator’s discretion. Maintenance treatment commences 3 weeks after the last dose of induction durvalumab.
Sponsors
The University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults aged 18 years and older, with treatment-naïve histologically confirmed (immunohistochemistry positive for Cam5.2, and/ or TTF1, Chromogranin, synaptophysin, with or without CD56 positivity) extensive-stage extra-pulmonary small cell carcinoma, not amenable to curative radiotherapy or surgical resection. 2. All efforts should be made to ensure sufficient and accessible tissue, including both FFPE and fresh biopsy (<90 days old) for molecular screening, PD-L1 immunohistochemistry assay and exploratory objectives, unless deemed unsuitable by the study physician in discussion with the lead PI of this substudy. In which case archival tissue is acceptable. However, there is no need to wait for MTB report for participant to be enrolled and study treatment commenced. 3. ECOG performance status 0-1. 4. One cycle of platinum (either cisplatin or carboplatin) and etoposide for extensive-stage extrapulmonary small cell carcinoma is allowed, within 3 weeks of enrolment. 5. If the CNS is involved, this must be controlled/ stable either with local treatment or by steroids (maximum 10 mg daily prednisone or equivalent dose of an alternative corticosteroid). 6. Measurable disease as assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) without prior radiotherapy to these sites. If radiotherapy was given to a single target lesion, there must be clear radiological evidence of progression of the lesion since completion of the radiotherapy. 7. Adequate organ system function as assessed by the following minimal laboratory requirements (within 14 days prior to first administration of study drug): a. Haemoglobin >= 9.0 g/L, Absolute neutrophil count (ANC) >=1.5 x 10^9/L), platelets >= 100 x 10^9/L, b. Liver function; ALT/AST <= 2.5 x ULN (in the absence of liver metastases, <= 5 x ULN for patients with liver involvement) and total bilirubin <=1.5xULN (except participants with Gilbert’s Syndrome, who are eligible with bilirubin <=2.5 ULN) c. Serum creatinine clearance >45 mL/min 8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments. 9. Signed, written informed consent to participate in this specific treatment substudy. 10. Life expectancy of at least 12 weeks. 11. Body weight >30kg.
Exclusion criteria
1. Prior systemic anti-cancer therapy for extensive-stage extrapulmonary small cell carcinoma, other than 1 cycle of platinum and etoposide given immediately prior to study registration. 2. Small cell transformation from other histology. 3. Large cell histology, including those of neuroendocrine origin, or small cell carcinoma of the ovary (hypercalcemic type). 4. Prior therapy with an anti-PD-1, anti-PD-L1 (including durvalumab), anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways. 5. Known history of hypersensitivity to active or inactive components or contraindications to durvalumab. 6. History of allergy or hypersensitivity to investigational product, cisplatin/ carboplatin, etoposide, or any excipient. 7. Participants with symptomatic or uncontrolled brain metastases or leptomeningeal disease are excluded. 8. 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], 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: a. Patients with vitiligo or alopecia. b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. c. Any chronic skin condition that does not require systemic therapy. d. Patients without active disease in the last 5 years may be included. e. Patients with celiac disease controlled by diet alone. 9. Any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 28 days of durvalumab administration. Intranasal, inhaled, or topical steroids or local steroid injections (e.g., intra-articular injection) are permitted in the absence of active autoimmune disease. Standard steroid premedication given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be counted for this criterion. 10. Current treatment or treatment within the last 12 months with any investigational anti-cancer products. 11. 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. 12. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 14 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception. 13. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) >= 470 msec in screening ECG measured using standard institutional method or history of familial long QT syndrome. 14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable. 15. No other malignancy that requires active treatment. Participants with a past history of adequately treated carcinoma in situ, non-melanoma skin cancer or lentigo maligna without evidence of disease or superficial transitional cell carcinoma of the bladder are eligible. 16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive cardiac failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, active peptic ulcer disease or gastritis, serious chronic gastrointestinal conditions associated with diarrhoea, active bleeding diatheses. 17. Hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions include past or resolved Hepatitis B (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) and patients positive for hepatitis C (HCV) antibody if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in absence of clinical suspicion of HIV. 18. Known history of primary immunodeficiency, allogeneic organ transplant, pneumonitis, or active tuberculosis. 19. Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30 days of receiving durvalumab. 20. Specific comorbidities or conditions or concomitant medications which may interact with the study treatment. 21. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 22. Serious medical or psychiatric conditions or social situation that might limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. 23. Any staff with involvement in the planning and/or conduct of the study. 24. Eligible for participation in another MoST substudy based on identification of an actionable mutation. Patients who have previously participated in another MoST substudy may subsequently participate in this study, all other inclusion and exclusion criteria being satisfied. 25. Participation in another clinical study with an investigational product during the last 4 weeks prior to study enrolment.
Outcome results
None listed