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Trial registered on ANZCTR


Registration number
ACTRN12621001225808
Ethics application status
Approved
Date submitted
12/08/2021
Date registered
13/09/2021
Date last updated
13/09/2021
Date data sharing statement initially provided
13/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Addendum 18 substudy 40: Durvalumab plus chemotherapy
Scientific title
A single-arm, open-label, signal-seeking, phase II trial of durvalumab and chemotherapy in patients with extra-pulmonary small cell carcinoma
Secondary ID [1] 305028 0
CTC0141- addendum 18
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 18
Linked study record
This record is an addendum to the MoST framework (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Extra-pulmonary small cell carcinoma 323199 0
Condition category
Condition code
Cancer 320781 320781 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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 oral capsule 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.
Intervention code [1] 321425 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328596 0
Progression free survival (PFS) at 12 months. Study participants who have stable disease, partial response or complete response confirmed at or beyond 12 months according to RECIST v1.,1 and iRECIST, will be considered to have attained PFS at 12 months. Disease response will be assessed by imaging (e.g. CT scans).
Timepoint [1] 328596 0
12 months from registration
Secondary outcome [1] 399582 0
Progression free survival (PFS). PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who did not progress or die will be censored on the date of their last clinical assessment or tumour assessment. Disease progression is defined according to RECIST v1.1.
Timepoint [1] 399582 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks post-treatment commencement until week 12 and then every 8 weeks until disease progression.
Secondary outcome [2] 399583 0
Objective tumour response rate (OTRR), defined by complete or partial response using RECIST v1.1 and iRECIST
Timepoint [2] 399583 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks post-treatment commencement until week 12 and then every 8 weeks until disease progression.
Secondary outcome [3] 399584 0
Depth of response, defined as the percentage of tumour shrinkage based on the sum of the longest diameters of all target lesions observed at the lowest point (nadir), compared with the sum of their diameters at baseline.
Timepoint [3] 399584 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks post-treatment commencement until week 12 and then every 8 weeks until disease progression.
Secondary outcome [4] 399585 0
Duration of response according to RECIST 1.1
Timepoint [4] 399585 0
Imaging (eg. CT scans) for disease evaluation will take place every 6 weeks post-treatment commencement until week 12 and then every 8 weeks until disease progression.
Secondary outcome [5] 399586 0
Overall survival (OS), OS at 12 months and OS at 18 months
Timepoint [5] 399586 0
From the date of registration to date of death from any cause, or the date of last known follow-up alive. OS at 12 months will be assessed 12 months from date of registration. OS at 18 months will be assessed 18 months from date of registration.
Secondary outcome [6] 399587 0
Safety and tolerability of treatment (rates of adverse events). Type, frequency, and severity of adverse events assessed by clinical assessment and/or participant self-report and documented in accordance with the Common Terminology Criteria for Adverse Events, (CTCAE5.0)
Timepoint [6] 399587 0
Adverse events will be recorded from first dose of study treatment until 30 days after the last dose of chemotherapy or until 90 days after the last dose of durvalumab, whichever is longer.
Secondary outcome [7] 399588 0
Health related quality of life during treatment assessed using the EORTC QLQ-C30 Form.
Timepoint [7] 399588 0
Every 3 weeks from first dose of study treatment during induction treatment phase and every 4 weeks during maintenance treatment phase until end of treatment. Subsequently, every 8 weeks until disease progression.
Secondary outcome [8] 399589 0
Health related quality of life during treatment assessed using The Brief Pain Inventory Form.
Timepoint [8] 399589 0
Every 3 weeks from first dose of study treatment during induction treatment phase and every 4 weeks during maintenance treatment phase until end of treatment. Subsequently, every 8 weeks until disease progression.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Total sample size for this MoST substudy is 16 patients. PFS12 observed in the platinum-doublet chemotherapy arms of CASPIAN and IMPOWER 133 studies in SCLC, was 5%, and that of chemo-immunotherapy was 12-18%.
A 12-month PFS rate of 18% supports the hypothesis for this trial. Using the method of Metha-Cain, boundaries for declaring activity was determined based on a one-sided 95% confidence interval for 12-month PFS rate which would include the hypothesized rate of 18%. Thus, for a sample size of 16 patients, we require 1 or more patients to be alive and progression-free at 12 months according to RECIST and iRECIST to conclude that study treatments demonstrate a promising signal of activity.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20230 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 20231 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment postcode(s) [1] 34962 0
2170 - Liverpool
Recruitment postcode(s) [2] 34963 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 309416 0
Government body
Name [1] 309416 0
Office for Health and Medical Research
Address [1] 309416 0
Locked Bag 961, North Sydney NSW 2059
Country [1] 309416 0
Australia
Funding source category [2] 309418 0
Other Collaborative groups
Name [2] 309418 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 309418 0
Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst NSW 2010
Country [2] 309418 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 310388 0
None
Name [1] 310388 0
Address [1] 310388 0
Country [1] 310388 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309219 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 309219 0
Translational Research Centre, 97-105 Boundary Street, Darlinghurst NSW 2010
Ethics committee country [1] 309219 0
Australia
Date submitted for ethics approval [1] 309219 0
31/05/2021
Approval date [1] 309219 0
10/08/2021
Ethics approval number [1] 309219 0
2021/ETH01107

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113386 0
Dr Peey Sei Kok
Address 113386 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050
Country 113386 0
Australia
Phone 113386 0
+61 2 8036 5232
Fax 113386 0
Email 113386 0
peey-sei.kok@sydney.edu.au
Contact person for public queries
Name 113387 0
Ms Sarah Chinchen
Address 113387 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050
Country 113387 0
Australia
Phone 113387 0
+61 2 95625000
Fax 113387 0
Email 113387 0
most.study@sydney.edu.au
Contact person for scientific queries
Name 113388 0
Dr Peey Sei Kok
Address 113388 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Levels 4-6, 92-94 Parramatta Rd,
Camperdown NSW 2050
Country 113388 0
Australia
Phone 113388 0
+61 2 9562 5000
Fax 113388 0
Email 113388 0
peey-sei.kok@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results